La Caixa Research Articles

OncodriveCLUSTL: a sequence-based clustering method to identify cancer drivers

This work was supported by funding from the Spanish Ministry of Economy and Competitiveness [SAF2015-66084-R, MINECO/FEDER, UE] and by the European Research Council [Consolidator Grant 68239]. IRB Barcelona is the recipient of a Severo Ochoa Centre of Excellence Award from the Spanish Ministry of Economy and Competitiveness (MINECO; Government of Spain) and is supported by CERCA (Generalitat de Catalunya). A.G.-P. is supported by a Ramon y Cajal contract from the Spanish Ministry of Economy and Competitiveness [RYC-2013-1455]. C.A.-P. is supported by “la Caixa” Foundation (ID 100010434) with code [LCF/BQ/ES18/11670011].

Data from: Fine scale spatial variability in the influence of environmental cycles on the occurrence of dolphins at coastal sites

Passive acoustic data were collected under a series of grants and contracts from DECC Offshore Energy Strategic Environmental Assessment Programme, Marine Scotland, Moray Offshore Renewables Ltd., The Crown Estate, Highlands and Islands Enterprise and Beatrice Offshore Wind Ltd. We thank Bill Ruck and colleagues from University of Aberdeen and Moray First Marine for fieldwork support. The tidal data was kindly provided by the United Kingdom Hydrographic Office. We would like to thank Dr Enrico Pirotta, Dr Julien Martin and Dr Barbara Cheney for their invaluable comments and ideas during the development of this work. We would also like to acknowledge the University of Aberdeen’s Maxwell computer cluster for assistance with the data processing. OFB was funded by “La Caixa” foundation and their support is gratefully acknowledged.

Dual Lysosomal-Mitochondrial Targeting by Antihistamines to Eradicate Leukemic Cells

Background: Despite great efforts to identify druggable molecular targets for hematological neoplasias, there remains an unmet need for more effective therapies. Methods: We screened FDA-approved drugs that may revert an early transformation gene signature. Hit compounds were validated in a primary in vitro screening, using AML cell lines. Cytotoxic and differentiation effect was determined both in primary AML patient samples and healthy donor blood cells. Xenotrasplantation assays were performed to determine the in vivo therapeutic effect of hit compounds. The mechanism of action responsible for the antileukemic effect was studied focussing on lysosomes and mitochondria. Findings: We identified a group of antihistamines (termed ANHAs) with distinct physicochemical properties associated with their cationic-amphiphilic nature, that selectively killed leukemic cells. ANHAs behaved as antileukemic agents against primary myeloid and lymphoblastic leukemia samples ex vivo, sparing healthy cells. Moreover, ANHAs severely impaired leukemic stem cell functionality in vivo. ANHAs' cytotoxicity relied on simultaneous mitochondrial and lysosomal disruption and induction of autophagy and apoptosis. The pharmacological effect was exerted based on their physicochemical properties that permitted the passive targeting of both organelles, without the involvement of active molecular recognition. Interpretation: Dual targeting of lysosomes and mitochondria has emerged as a new promising therapeutic approach for eradication of leukemia. Funding Statement: RMR is supported by Ramon y 47 Cajal program of the Spanish Ministry of Economy (RYC-2011-07998 and IEDI-2016-00740), and JMCM is supported by Fundacion Mutua Madrilena. This work was funded by the Fundacion Mutua Madrilena (RMR), CaixaImpulse CI16-00003 (RMR), SAF2015-66721-P from MINECO (RMR), the Josep Carreras International Leukaemia Foundation (RMR), l’Obra Social “La Caixa”-Fundacio Bancaria “La Caixa” (RMR), and CERCA Programme/Generalitat de Catalunya (IJC). Declaration of Interests: RMR is a shareholder of Leukos Biotech. No other conflicts of interest reported. Ethical Approval Statement: All patients provided written informed consent in accordance with the Declaration of Helsinki, and the study was approved by the corresponding Ethics Committees (Ethics ommittee Hospital Clinic de Barcelona, Ethics Committee Hospital Germans Trias i Pujol). All experiments involving mice were approved by the Catalan Ethical Committee of Animal Experimentation (CCEEA).

APOA1 oxidation is associated to dysfunctional high-density lipoproteins in human abdominal aortic aneurysm

BackgroundHigh-density lipoproteins (HDL) are a complex mixture of lipids and proteins with vasculoprotective properties. However, HDL components could suffer post-translational modifications (PTMs) under pathological conditions, leading to dysfunctional HDL. We studied whether HDL are modified in abdominal aortic aneurysm (AAA) and the effect on HDL functionality.MethodsHDL were isolated by ultracentrifugation from AAA tissue (HDL-T) and from plasma of healthy volunteers and then incubated with AAA tissue-conditioned medium (HDL-AAA CM). PTMs from these particles were characterized using Comet-PTM. The ability of HDL-AAA CM for promoting cholesterol efflux was determined ex vivo and in vivo by using J774A.1 [3H]cholesterol-labeled mouse macrophages and after injecting [3H]cholesterol-labeled mouse macrophages and HDL into the peritoneal cavity of wild-type C57BL/6 mice, respectively. Trp50 and Trp108 oxidized forms of APOA1 in HDL incubated with conditioned-medium of activated neutrophils and in plasma of AAA patients and controls were measured by targeted parallel reaction monitoring.FindingsOxidation was the most prevalent PTM in apolipoproteins, particularly in APOA1. Trp50 and Trp108 in APOA1 were the residues most clearly affected by oxidation in HDL-T and in HDL-AAA CM, when compared to their controls. In addition, cholesterol efflux was decreased in macrophages incubated with HDL-AAA CM in vitro and a decreased macrophage-to-serum reverse cholesterol transport was also observed in mice injected with HDL-AAA CM. Finally, both oxidized Trp50 and Trp108 forms of APOA1 were increased in HDL incubated with conditioned-medium of activated neutrophils and in plasma of AAA patients in relation to controls.InterpretationOxidative modifications of HDL present in AAA tissue and plasma were closely associated with the loss of vasculoprotective properties of HDL in AAA.FundMINECO, ISCiii-FEDER, CIBERDEM, CIBERCV and LA CAIXA.

Olfactory proteotyping: towards the enlightenment of the neurodegeneration.

Olfactory proteotyping: towards the enlightenment of the neurodegeneration.

Characteristics and Outcome of Early T Cell Precursor ALL (ETP-ALL) Patients Treated with High-Risk Spanish Pethema Protocols

▪Background:ETP-ALL was included as a provisional identity in the 2016 WHO classification of ALL. This subtype was first identified by Coustan-Smith et al. in 2009. However, this immunophenotype-based classification does not fully enclose all ETP-ALL cases identified by gene expression profile (GEP). Although early studies in small series of ETP-ALL suggested a very poor outcome for ETP ALL more recent and larger series have showed improvement in outcome treating children with a contemporary protocol based on chemotherapy schedules, or after allogeneic stem cell transplantation (allo-SCT) in adults.Aim:To investigate the clinical and biological features of ETP-ALL cases in the Spanish cohort of adult T-cell ALL (T-ALL) patients and to assess the potential impact of high-risk therapy on their outcome.Method:One hundred eighty-five adults with T-ALL treated according to two consecutive MRD-oriented high-risk adult PETHEMA protocols -ALL-HR-2003 (NCT00853008) and ALL-HR-11 (NCT01540812; still ongoing)- were included in this study. The EGIL criteria were used to define the immunologic subtype of T-ALL after central review of immunophenotype reports, and the criteria proposed by Zuurbier et al. (Zuurbier L. et al. Haematologica 2014; 99:94-102) were used to define ETP-ALL. These later criteria consist of a combination of immunophenotypic markers (absence of CD1a-/CD4-/CD8-, cut-off <10%, and expression of the stem cell marker CD34+and/or at least one myeloid marker such as CD13+or CD33+, cut-off >25%), that resemble those published by Coustan-Smith, with the advantage that include most ETP-ALL cases, as identified by GEP, avoiding the use of partial expression of CD5 marker to immuno-classify these patients.Results:Thirty-four out of 167 evaluable patients (20%) with T-ALL showed an ETP-ALL immunophenotype. Patients with ETP-ALL were older (mean 39 [SD 12] vs. 33 [12] yr; p=0.011), showed more frequently lymph node involvement (79% vs. 56%; p=0.021) and lower WBC counts at diagnosis (mean, 72 [155] vs. 97 [112] x109/L; p=0.004). At genetic level, ETP-ALL patients were associated with the absence of deletions in CDKN2A/B gene cluster (91% vs. 26%; p<0.001) (10/11 cases) and with the absence of bi-allelic deletions in TCRG gene (67% vs. 5%; p=0.001) (6/9 cases). In turn, ETP-ALL patients showed poorer response to induction therapy: 82% of ETP-ALL had poorer early cytologic response (>10% BM blasts on day+14) vs. 37% of non-ETP (p<0.001), and 23% of ETP-ALL patients did not reach CR vs. 6% non-ETP T-ALL cases (p=0.005). Flow-MRD data at CR (available in 141/167 patients) showed MRD levels ≥0.1% in 65% of ETP-ALL vs. 18% of non-ETP ALL (p<0.001), and MRD level ≥0.01% in 85% vs. 37%, respectively (p<0.001). Forty-six percent of ETP-ALL patients required a second induction treatment compared to 8% of non-ETP-ALL (p<0.001). Consequently, more ETP-ALL patients underwent allo-SCT (70% vs. 21%, p<0.001). The OS of ETP-ALL patients was poorer after censoring or not the follow-up at the time of transplant (Figures 1A and B).Conclusions:ETP-ALL accounts for 20% of adult T-ALL in the PETHEMA cohort and it is associated with a poorer initial response to treatment (lower CR rate, poorer MRD clearance) than the remaining T-ALL patients. Such poorer outcome is not overcome by allo-SCT in our series.Supported by grants from: Asociación Española Contra el Cáncer, AECC (GC16173697BIGA), Instituto Carlos III (PI14/01971 FI), 2017-SGR288 (GRC), CERCA Program from Generalitat de Catalunya, and “La Caixa” Foundation. [Display omitted] DisclosuresMontesinos:Daiichi Sankyo: Consultancy, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

Comparison of Clinical Characteristics and Prognosis of a Series of Patients from the Spanish Registry of MDS Diagnosed with Myelodysplastic/Myeloproliferative Neoplasms According to the 2016 Reviewed Classification of the World Health Organization

Background: The 2016 reviewed classification of the World Health Organisation (WHO) defines a group of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) including the chronic myelomonocytic leukemia (CMML), the myelodyplastic syndrome with ring sideroblasts and thrombocytosis (MDS-RS-T) and the MDS/MPN unclassifiable (MDS/MPN-U). The presence of typical clinical characteristics of MDS and MPN hinders the diagnosis and the prognosis of MDS/MPN-U.Aim: The objective of this study was to compare the clinical characteristics and the prognosis of a series of patients with MDS/MPN such as CMML, MDS-RS-T and MDS/NPM-U from the Spanish registry of MDS.Method: We analized 107 patients diagnosed with MDS/MPN (MDS-RS-T, MDS/NPM-U and CMML) according to the 2016 WHO classification. A comparison of the clinical characteristics, overall survival (OS) and cumulative incidence of progression (CIP) was performed.Results: Median (range) age was 74 (23-93) years and 68/107 (64%) were males. The number of patients in each group was: MDS-RS-T (n=45), MDS/MPN-U (n=29) and CMML (n=33). The main clinical characteristics of the three groups are described in Table 1. There were significant statistical differences in hemoglobin and lactate dehydrogenase levels and leukocyte, monocyte and platelet counts between the three groups. With a median (range) of follow-up of 3.1 (0.3-19.3), 3.7(0.7-10.4) and 4 (1.8-8.5) years for MDS-RS-T, MDS/MPN-U, and CMML, respectively, the OS (95%CI) at 5 years was significantly better in patients with MDS-RS-T (61% [42%; 80%]) compared to MDS/MPN-U and CMML patients (21% [1%; 41%] and 19% [3%; 35%], p=0.002) (Figure 1). The CIP (95%CI) at 5 years between the three groups was significantly different: MDS/MPN-U and CMML (40% [18%; 61%] and 32% (14%-52%, respectively) vs. MDS/RS-T 8% [0.4%; 30%]) (p=0.005) (Figure 2).Conclusions: 1) In this series of patients with MDS/MPN (MDS-RS-T, MDS/MPN-U and CMML) according to the 2016 WHO classification clinical characteristics were similar except for hemoglobin and lactate dehydrogenase levels and leukocyte, monocyte and platelet counts. 2) Patients with MDS-RS-T had longer OS and less CIP than those with MDS/MPN-U and CMML; 3) The prognosis of MDS/MPN-U and CMML were similar.Supported by grants from: AGAUR 9015-470120/2015, 2017-SGR288 (GRC), CERCA Program from Generalitat de Catalunya, and “La Caixa” Foundation. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Integrin-linked kinase (ILK) and src homology 2 domain-containing phosphatase 2 (SHP2): Novel targets in EGFR-mutation positive non-small cell lung cancer (NSCLC).

BackgroundThe activation of multiple signaling pathways jeopardizes the clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutation positive non-small cell lung cancer (NSCLC). Integrin-linked kinase (ILK) regulates the interactions between tumor cells and extracellular environment to activate signaling pathways and promote cell proliferation, migration, and epithelial-mesenchymal transition. Src homology 2 domain-containing phosphatase 2 (SHP2) is essential for receptor tyrosine kinase signaling and mitogen-activated protein kinase (MAPK) pathway activation.MethodsWe analyzed tumor ILK, β-receptor subunit glycoprotein 130 (gp130), SHP2, and stromal hepatocyte growth factor (HGF) and interleukin-6 (IL-6) mRNA expression in baseline tumor specimens of advanced EGFR-mutation positive NSCLC patients treated with EGFR TKIs.ResultsILK, when highly expressed, was an independent poor prognostic factor for the progression-free survival of the patients, both in the univariate (hazard ratio [HR for disease progression, 2.49; 95% CI, 1.37–4.52; P = .0020]) and in the multivariate (HR 3.74; 95% CI, 1.33–10.56; P = .0126) Cox regression model. Patients with high SHP2 expression had an almost 13-month shorter progression-free survival (P = .0094) and an 18-month shorter overall survival (P = .0182) in comparison to those with low SHP2 mRNA expression.InterpretationThe levels of ILK and SHP2 could be predictive for upfront combinatory therapy of EGFR TKIs plus SHP2 or ILK inhibitors.FundA grant from La Caixa Foundation, an Instituto de Salud Carlos III grant (RESPONSE, PIE16/00011), an Instituto de Salud Carlos III grant (PI14/01678), a Marie Skłodowska-Curie Innovative Training Networks European Grant (ELBA No 765492) and a Spanish Association Against Cancer (AECC) grant (PROYE18012ROSE).

Plasma and CSF biomarkers for the diagnosis of Alzheimer's disease in adults with Down syndrome: a cross-sectional study

Diagnosis of Alzheimer's disease in Down syndrome is challenging because of the absence of validated diagnostic biomarkers. We investigated the diagnostic performance of plasma and CSF biomarkers in this population. We did a cross-sectional study of adults aged 18 years and older with Down syndrome enrolled in a population-based health plan in Catalonia, Spain. Every person with Down syndrome assessed in the health plan was eligible to enter the Down Alzheimer Barcelona Neuroimaging Initiative, and those with a plasma or CSF sample available were included in this study. Participants underwent neurological and neuropsychological examination and blood sampling, and a subset underwent a lumbar puncture. Adults with Down syndrome were classified into asymptomatic, prodromal Alzheimer's disease, or Alzheimer's disease dementia groups by investigators masked to biomarker data. Non-trisomic controls were a convenience sample of young (23-58 years) healthy people from the Sant Pau Initiative on Neurodegeneration. Amyloid-β (Aβ)1-40, Aβ1-42, total tau (t-tau), 181-phosphorylated tau (p-tau; only in CSF), and neurofilament light protein (NfL) concentrations were measured in plasma with a single molecule array assay and in CSF with ELISA. Plasma and CSF biomarker concentrations were compared between controls and the Down syndrome clinical groups. Diagnostic performance was assessed with receiver operating characteristic curve analyses between asymptomatic participants and those with prodromal Alzheimer's disease and between asymptomatic participants and those with Alzheimer's disease dementia. Between Feb 1, 2013, and Nov 30, 2017, we collected plasma from 282 participants with Down syndrome (194 asymptomatic, 39 prodromal Alzheimer's disease, 49 Alzheimer's disease dementia) and 67 controls; CSF data were available from 94 participants (54, 18, and 22, respectively) and all 67 controls. The diagnostic performance of plasma biomarkers was poor (area under the curve [AUC] between 0·53 [95% CI 0·44-0·62] and 0·74 [0·66-0·82]) except for plasma NfL concentrations, which had an AUC of 0·88 (0·82-0·93) for the differentiation of the asymptomatic group versus the prodromal Alzheimer's disease group and 0·95 (0·92-0·98) for the asymptomatic group versus the Alzheimer's disease dementia group. In CSF, except for Aβ1-40 concentrations (AUC 0·60, 95% CI 0·45-0·75), all biomarkers had a good performance in the asymptomatic versus prodromal Alzheimer's disease comparison: AUC 0·92 (95% CI 0·85-0·99) for Aβ1-42, 0·81 (0·69-0·94) for t-tau, 0·80 (0·67-0·93) for p-tau, and 0·88 (0·79-0·96) for NfL. Performance of the CSF biomarkers was optimal in the asymptomatic versus Alzheimer's disease dementia comparison (AUC ≥0·90 for all except Aβ1-40 [0·59, 0·45-0·72]). Only NfL concentrations showed a strong correlation between plasma and CSF biomarker concentrations in participants with Down syndrome (rho=0·80; p<0·0001). Plasma NfL and CSF biomarkers have good diagnostic performance to detect Alzheimer's disease in adults with Down syndrome. Our findings support the utility of plasma NfL for the early detection of Alzheimer's disease in Down syndrome in clinical practice and clinical trials. Institute of Health Carlos III, Fundació La Marató de TV3, Fundació Bancaria Obra Social La Caixa, Fundació Catalana Síndrome de Down, and Fundació Víctor Grífols i Lucas.

Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicentre, retrospective analysis

Anti-programmed death-1 (PD-1) treatment for advanced non-small-cell lung cancer (NSCLC) has improved the survival of patients. However, a substantial percentage of patients do not respond to this treatment. We examined the use of DNA methylation profiles to determine the efficacy of anti-PD-1 treatment in patients recruited with current stage IV NSCLC. In this multicentre study, we recruited adult patients from 15 hospitals in France, Spain, and Italy who had histologically proven stage IV NSCLC and had been exposed to PD-1 blockade during the course of the disease. The study structure comprised a discovery cohort to assess the correlation between epigenetic features and clinical benefit with PD-1 blockade and two validation cohorts to assess the validity of our assumptions. We first established an epigenomic profile based on a microarray DNA methylation signature (EPIMMUNE) in a discovery set of tumour samples from patients treated with nivolumab or pembrolizumab. The EPIMMUNE signature was validated in an independent set of patients. A derived DNA methylation marker was validated by a single-methylation assay in a validation cohort of patients. The main study outcomes were progression-free survival and overall survival. We used the Kaplan-Meier method to estimate progression-free and overall survival, and calculated the differences between the groups with the log-rank test. We constructed a multivariate Cox model to identify the variables independently associated with progression-free and overall survival. Between June 23, 2014, and May 18, 2017, we obtained samples from 142 patients: 34 in the discovery cohort, 47 in the EPIMMUNE validation cohort, and 61 in the derived methylation marker cohort (the T-cell differentiation factor forkhead box P1 [FOXP1]). The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0·010, 95% CI 3·29 × 10-4-0·0282; p=0·0067) and overall survival (0·080, 0·017-0·373; p=0·0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0·330, 0·149-0·727; p=0·0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0·415, 0·209-0·802; p=0·0063) and overall survival (0·409, 0·220-0·780; p=0·0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy. Our study shows that the epigenetic milieu of NSCLC tumours indicates which patients are most likely to benefit from nivolumab or pembrolizumab treatments. The methylation status of FOXP1 could be associated with validated predictive biomarkers such as PD-L1 staining and mutational load to better select patients who will experience clinical benefit with PD-1 blockade, and its predictive value should be evaluated in prospective studies. "Obra Social" La Caixa, Cellex Foundation, and the Health and Science Departments of the Generalitat de Catalunya.

Centre for Genomic Regulation - a hub for Integrative Biology in Barcelona.

Centre for Genomic Regulation - a hub for Integrative Biology in Barcelona.

PLCG2 Protective Variant p.P522R Modulates Tau Pathology and Disease Progression in Patients with Mild Cognitive Impairment

Background: A rare coding variant (rs72824905, p.P522R) conferring protection against the susceptibility to Alzheimer's disease (AD) was recently identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2). Here, we explore the protective nature of this variant with regard to AD pathology indicated by biomarkers, cognitive decline, and potential underlying biological mechanisms. Methods: Association of p.P522R with CSF levels of pTau181, total Tau and Aβ1-42 was assessed in 1,282 patients with mild cognitive impairment (MCI) or AD-dementia syndrome. In addition, the association with longitudinal cognitive decline was tested in 3,010 MCI patients from memory clinic cohorts and 10,100 individuals from population-based studies using latent process linear mixed models. Finally, unsupervised co-trans-regulatory network analysis and biological experiments were conducted. Findings: Carriers of the p.P522R variant showed lower pTau181 levels in CSF compared to non-carriers, specifically in the presence of amyloid pathology. In MCI patients but not in population-based cohorts, the p.P522R variant was associated with slower cognitive decline with an effect size similar to that of APOE-e4. We identified a network of coregulated proteins linking PLCG2 to APOE and TREM2. Finally, in vitro experiments confirmed that inflammasome activation upon phospholipase C stimulation might act downstream of PLCG2. Implication: Our data link the protective effect of p.P522R in PLCG2 to reduced Tau pathology, to a slower cognitive decline in MCI patients and to underlying inflammatory processes. Therapies targeting the enzyme PLCG2 might provide a therapeutic approach for AD. Funding Statement: EU Joint Programme Neurodegenerative Disease Research, Innovative Medicines Initiative 2, Instituto de Salud Carlos III, La Caixa, Grifols SA, German Federal Ministry of Research and Education, Sanofi Laboratories, Fondation pour la Recherche Medicale, Fondation Plan Alzheimer, Stichting Alzheimer Nederland, Stichting VUmc fonds, Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care, Netherlands Organization for Scientific Research (NWO), EMGO+ Research Institute. Declaration of Interests: All authors report no conflict of interest. PL received consultation and/or lecture honoraria from IBL International, Fujirebio Europe, AJ Roboscreen, and Roche. JW received honoraria for consulting activities, lectures or advisory board participation from Pfizer, Eli Lilly, Hoffmann-La-Roche, MSD Sharp + Dome, Janssen-Cilag GmbH, Immungenetics AG, Boehringer Ingelheim. LF received honoraria for consulting activities, lectures or advisory board participation from Allergan, Eli Lilly, Avraham Pharmaceuticals, Axon Neuroscience, Axovant, Biogen, Boehringer Ingelheim, Eisai, Functional Neuromodulation, Lundbeck, MerckSharpe & Dohme, Novartis, Pfizer, Pharnext, Roche, Schwabe Pharma; he served on Data and Safety Monitoring boards or endpoint committees with Avraham Pharmaceuticals, Axon Neuroscience, Forschungszentrum Julich, Novartis, Pharmatropix. JP received honoraria for consulting activities, lectures or advisory board participation from Fujirebio Europe, Ono Pharma, Eli Lilly, and Nestle Institute of Health Sciences. ARu reports consulting Fees: Landsteiner Genmed, Grifols, Araclon biotech. And Lecture Fees: Araclon Biotech.PA reports personal fees from Servier, Total, Genoscreen, Takeda, Foundation Alzheimer. OP received research funding, consultancy fees or speech honoraria from Axovant, Biogen, Genentech, Lilly, Lundbeck, Novartis, Pharmatrophix, Piramal, Probiodrug, Roche, Takeda and TauRx Pharmaceuticals. MB receives fees or has received for consulting from Lab. Servier, Roche, Lilly, Avid, Bayer, Elan, Janssen, Neuroptix, Sanofi. She receives or has received fees for lectures from Lilly, Nutricia, Roche, Schwabe, Araclon, Esteve, Grifols, Janssen, Novartis, Piramal, Pfizer-Wyett, Servier. She receives fees for being part of the Advisory Board of Lilly and Schwabe. She reports grants/research funding from Abbvie, Araclon, Biogen Research Limited, Bioiberica, Grifols, Lilly, S.A, Merck Sharp & Dohme, Kyowa Hakko Kirin, Laboratorios Servier, Nutricia SRL, Oryzon Genomics, Piramal Imaging Limited, Roche Pharma SA, and Schwabe Farma iberica SLU, all outside the submitted work. She has not received personal compensations from these organizations Ethics Approval Statement: The individual studies were approved by the respective ethics committees.

Contribution of bioactive hyaluronic acid and gelatin to regenerative medicine. Methodologies of gels preparation and advanced applications

Authors thank CIBER-BBN, Spain and the Spanish Ministry of Economy and Competitivity (project MAT2014-51918-C2-1-R and M. Puertas-Bartolome scholarship) and “la Caixa” Foundation (A. Mora-Boza scholarship) for supporting this work

Educación, salud y pobreza. Programa CaixaProInfancia en Murcia: Estudio de casos

Introducción: Los informes sobre pobreza en España muestran la situación en la Comunidad Autónoma de la Región de Murcia y su incidencia en la infancia, en sus condiciones de vida, en su salud física, mental y social (UNICEF, 2012; FOESSA y Cáritas, 2014; Save the Children, 2015; EAPN-ES, 2012, 2016; Observatorio de Sostenibilidad, 2016). En España, la Obra Social de la Fundación “la Caixa” puso en marcha el programa CaixaProinfancia (CPI) para dar apoyo socioeducativo la infancia y sus familias, en situación de vulnerabilidad por causa de la pobreza. Este estudio forma parte de un proyecto más amplio, liderado por el grupo PSITIC de la Universidad Ramón Llull. Objetivo: Conocer los efectos que está produciendo el programa en la educación y en la salud de las familias e infancia, en situación de pobreza y vulnerabilidad social, en la Región de Murcia. Metodología: cualitativa, se concreta en la realización de un “estudio de casos”. Datos: muestran la mejora en sus condiciones de vida y en la salud de la infancia y sus familias. Conclusión: Quienes han participado están muy satisfechos por los beneficios obtenidos, así como con quienes lo desarrollan (profesionales). Proponen nuevas actuaciones en educación sexual, alimentación, deporte y orientaciones educativas con los hijos e hijas.

(Dis)fluency markers in dementia: how much can errors tell us?

(Dis)fluency markers in dementia: how much can errors tell us?

Integrated care for mental health social inclusion through job placement: Implementing IPS in Spain

Introduction: Individual Placement and Support (IPS) is an integrated social, labor and mental health intervention with an important component of evidence for its effectiveness in helping people with severe mental disorders. Its objective is to obtain and maintain competitive jobs, increase social inclusion and quality of life, and while consuming fewer resources. In Europe, IPS model (which began 14 year ago) is currently implemented in four countries which share background with Dartmouth College. This work aims to describe achievements and challenges of IPS implementation in Catalonia, Spain. Back in 2013, the project started with an agreement among three Regional Government Departments (Ministry of Health, Ministry of Business and Labor, and Ministry of Social Wellbeing and Family), “la Caixa” Banking Foundation, Government of Province of Barcelona, and the Dartmouth Psychiatric Research Center. The goal of the project is to improve labor and social inclusion of people with mental disorders, with a pilot project of the integrated plan of care for people with mental illness and addictions (2014-2016), as one of the strategies to promote ordinary labor inclusion for people with severe mental disorders. Practice change implemented: The project aims to integrate efforts and workflow from three areas (health care, social services and labor) both at community and policy levels to develop supported employment. It is based on IPS principles, such as: zero exclusion criteria; personalized benefits counseling; competitive jobs; IPS and mental health services integration; rapid job search; IPS professionals building relationships with employers; continuous supports and follow-up’s; and respect clients’ preferences. The innovative challenge involves implementing a new community perspective to support people with severe mental disorders finding a job and keeping it. Changes implemented are based on a specific patient management system including integration of Employment Programs with mental health treatment teams, interventions at community level and in the workplace including local employers. They are measured through a “fidelity scale” validated by Dartmouth College. Facing stigma and social barriers for inclusion are also included. Actions taken include: 1) professional training, as specific competencies are needed to be developed in different professionals’ roles to work in multidisciplinary teams; 2) improving workflow integration between mental Health and Employment Services including periodic meetings, patient plans and training on benefits planning and coordination among main administrators; 3) on-site support and monitoring achievements through an ICT platform that allows on-time review of results; 4) quarterly follow-up meetings among regional leaders, Mental Health teams and Employment Services to identify opportunities for improvement and support and encourage local development. In addition, an individualized action plan is developed to improve practices in each Employment Service. Key findings: Since October 2013, 7 sites have adapted their own programs to implement IPS methodology in Catalonia. Up to June 2015, an average of 350 people with severe mental illness has participated in these programs quarterly. Although severe economic crisis, percentage of working people have increased 17.7% from the beginning of the program. The number of jobs found by people during this period is 344. Although first fidelity reviews (which measure adherence of work process proposed by IPS methodology) were poor, now they have increased 18.8% as average. Highlights: Main barriers found in implementation process are related to economic crisis background and stigma for people with mental illness; adoption of innovation, current funding for programs development, different reported indicators for different funding sources, and the need of further integration among Employment Services and Mental Health Agencies, including the lack of shared electronic records with confidentiality implications Facilitators involve strong government support for the pilot project, periodic follow up and facilitator support approach, friendly professionals’ network created, as well as their commitment to increase patients’ quality of life. Improving communication among services is a key practice to increase access to multidisciplinary resources, with a strong senior leadership that supports the integration of different services in a variety of levels. Conclusions: A strong local leadership and commitment is fostering the project with a territorial approach, and raising IPS as an important intervention to obtain and maintain competitive employment and recovery for people with a mental health condition. To achieve this goal, payment systems will probably need to be aligned. The possibility of a European Collaborative Network to share these practices and knowledge may improve sustainability and implementation in a European context, and allow testing its effectiveness in other patients groups.

ACTIVA´T PER LA SALUT MENTAL: patients and caregivers as managers for integration of care and services in Mental Health

Activa´t per salut mental : patients and caregivers as managers for integration of and services in Mental Health main goal of project ACTIVA’T PER LA SALUT MENTAL(“Get active for mental health””) is to promote people with mental disorders and caregivers as managers of own integrated care. It’s apilot project for three years to address the gaps identified in order to consolidate a specific service in the portfolio of public services. project is a partnership formed by professionals, family members and people with severe mental disorders, developed jointly by the Catalan Federation of Mental Health and the Health Department of the Catalan Government, in collaboration with 12 local mental services and12 families and users associations. In Catalonia 54 714 people with severe mental disorders have been attended in 2014, 32.2% of the total at mental centers for adults. Mental disorders influence in on all family members: between 40% and 90% of people with mental disorders live in or have frequent and close contact with their families, who provide physical and emotional support at long term. Catalan government prioritizes public policies for family and empowerment in Mental Health from the regulatory framework (PINSAP - Interministerial Public Health Plan; PIAISS - Interdepartmental Plan for Care and Social and Health Interaction; Health Plan 2011-15; Plan for Mental Health and Addictions; and Integral Mental Health Plan), and from studies that recognize deficiencies: The relationship between users and professionals in the field of mental health (2007); Needs of family care (Dep. Health, 2009); Itineraries in mental health: needs of users and their families in the therapeutic (Health Department 2010). Aims : - Provide useful tools for the daily management of mental disorders for families and people with mental problems and promoting their own mental health. - Increasing the degree of influence and control that families and people with mental problems play on their own lives and processes of recovery, and their participation in the Health System. - Develop spaces that improve social cohesion as a tool to reduce vulnerability for families and people with mental problems, through the establishment of peer support iniciatives. - Encourage joint action of health, social, advocacy and other networks to ensure the adequacy and continuity of care. - Assess the results and measure the impact of the program in relation to its objectives. Methodology : A common circuit is developed with a continuum of services from the vision to the social-based community approach: - Psychoeducative training for people with mental problems (Klau de Re) and family (PROENFA), by mental services. - Training on empowerment (PROSPECT) for people with mental problems, families, and and social professionals, by the advocacy groups. - Participation in peer support groups for people with mental problems and their families, by the advocacy groups A shared professional, integrated in networks, coordinates the circuit. He acts as a referent for information on mental issues on the basis of a comprehensive vision, accessibility and active listening. All support tools used at the project are validated (training programs, brochures, guides...) evaluation strategy focuses on outcomes at three levels: the family, the person with mental problems and the impact on the system,. Key findings : - Implementation has started in 12 Catalan cities in partnership with mental centers and associations of users and families, and the centralized information service at the Federation. - 220 people ( 110 families) have been surveyed. - More than 500 inquiries have been attended from February 2015. Highlights : - Great interest among the different stakeholders - Difficulties during the recruitment process to attract participants respecting strict criteria. - great need identified is not associated with a sign of commitment and availability for training. - Integrating social local networks and system has been difficult but successful in all pilot locations. - Integration of diferent information sources (administrative data bases and outcomes surveys) allow a precise diagnosis of the situation of family units Conclusions : - Results available in September 2016. - project is deployed in 12 different municipalities, but the results are transferable since it works with approved materials. - It is sustainable because it reduces public costs, addressing individual needs as a group, and, improving the tools to be autonomous in recovery, reduce the need for care. Collaboratos : Active for mental health project recieves the support of the four Catalan Province Councils, the Barcelona City Council, the Ministry of Health, Social Services and Equality, and Ivalua; and it’s has also private financingt by Obra Social la Caixa, Otsuka, Lundbeck, Janssen Roca i Pi Foundation, Roviralta Foundation and Roca Salvatella.

Actua, tots per tots (act, all for all)

This abstract describes a self-advocacy program for people with mental health conditions. The programme called “ACTUA, TOTS PER TOTS“ (ACT, ALL FOR ALL) has been designed and implemented by ATRA, an association with 30 years of experience in the treatment and care of people with mental disorders, addictive behavior and at risk of social exclusion. Key characteristics of the programme are the participation of volunteers with and without mental disorder.After 15 months of implementation, 30 persons have been attended with positive results and 23 volunteers have been involved.This INNOVATIVE program supports independent living for people with mental illness by incorporating the participation of volunteers with and without mental disorder. Participation of volunteers with mental illness positively enriches the program because it encourages cooperation and mutual support among people with the same challenges and experiences. Empowering these participants also helps to break down the stigmas associated with mental illnesses. It helps them build their confidence and self-esteem. All the volunteers, those with or without disease, share tasks and responsibilities to support people with mental disorders, who live alone or with their family and need supervision to maintain stability his/her disease and to live a normal life.The program was initiated based on two key data points. First, there was a need detected by professionals. Secondly, it considered a study by the local mental health service (CSMA) that identified an additional 103 possible beneficiaries of this program.The program aims to promote independence, improve quality of life, empower people with disabilities arising from mental illness, enhance the process of rehabilitation and facilitate patient’s integration to the community. Specifically, it is an answer to the unmet need for guidance and support in performing activities for daily life with the objective being that the patients themselves are beneficiaries, as well as participants in their rehabilitation to a normal life.The ACTUA, TOTS PER TOTS program develops innovative and social transformative practices which are easily reproducible, making them available and transferable to other municipalities, countries and regions. It leverages an integrated approach to the individual and his/her needs with all actions aimed at his/her empowerment and full social inclusion. The beneficiaries have an active indispensable participation in the process from the very design of their PAP (personal attention program), which targets working within different areas of daily life: self-care, community skills, occupational and social Relations and domestic skills.Key elements of the Program:1.The team of "ACTUA, TOTS PER TOTS” is composed of two professionals with extensive experience within the field of Mental Health.2.Volunteers play a key role in the development of this program and training is a crucial aspect. All volunteers receive training prior to any involvement in the program, as well as continuous training throughout their involvement in the program. Each volunteer is assigned a number of beneficiaries, debriefed on the beneficiaries’ PAP objectives and responsible for making home visits, with a frequency dependent on the needs of the person assigned.3.The networking. Fluid and open-communication between the different professionals treating the person is indispensable.The program began in July 2014 thanks to the support received from the Obra Social La Caixa and Diputació de Barcelona. In 2015, ATRA also received a grant from the Generalitat de Catalunya.Results of the first 15 months of implementation: Today, we attended to 30 people with mental disease from Garraf County. They receive support through individualized, custom-attention (tutoring with volunteers and professionals) and group care (professionals). ATRA also works with families at both the individual and group level. To date, we have successfully detected eight cases where individuals were not following the prescribed pharmacologic treatment properly, two cases of Diogenes syndrome, two psychiatric admissions were avoided, 17 people have started leisure activities, three people were suspected and confirmed to have addiction problem, and three people went back to study. Finally, we have supported four people mourning the death of a family member. Each month the list increases, highlighting the effectiveness of the program.Currently, ATRA has 23 volunteers participating in the program, eleven of them with mental illness. The message the volunteers gives is “If I can do it, you can do it also”.Conclusions: People who participate in the program improve in the different areas of their PAP.Volunteers, help and support others, empower participants, fight the stigma of mental illness and increase social awareness. Sharing their experiences gives them the opportunity to show themselves as people and show everything they can do without constraints they often feel when diagnosed with a mental health problem.

Promoviendo la participación juvenil desde la comunidad

Este trabajo presenta el inicio de una experiencia socioeducativa con población joven que tiene la pretensión de potenciar su protagonismo en la comunidad, dinamizando al colectivo juvenil para que sea éste mismo quién organice y gestione su ocio y tiempo libre. La iniciativa parte de un estudio previo, la Monografía Comunitaria (Vecina, Segura y Alomar, 2015), elaborado a partir de una Investigación Participativa y de una Programación y Diagnóstico Comunitario, en cuyas conclusiones se plantean retos de la comunidad que deben ser abordados desde sus protagonistas. Una de estas líneas implica a la población joven como un colectivo alienado del contexto en el que habita, un espacio urbano que poco a poco se ha ido convirtiendo en un lugar destinado al ocio y consumo turístico, quedando parte de la población residente y sus necesidades cotidianas al margen de este proceso de gentrificación. La iniciativa se enmarca en el Proyecto de Intervención Comunitaria Intercultural (ICI) impulsado por la Obra Social “la Caixa”, gestionado en Palma (islas Baleares) por la asociación GREC y la colaboración del Ayuntamiento. Se trata de uno de los 39 territorios de toda España en el que se implementa este proyecto. Sus objetivos generales son fomentar la convivencia, la cohesión social, favorecer el desarrollo local y mejorar las condiciones de vida de la población.

Enhancing psychosocial and spiritual palliative care: Four-year results of the program of comprehensive care for people with advanced illnesses and their families in Spain.

We aimed to describe the overall quantitative and qualitative results of a "La Caixa" Foundation and World Health Organization Collaborating Center Program entitled "Comprehensive Care for Patients with Advanced Illnesses and their Families" after four years of experience. Qualitative and quantitative methods were employed to assess the program. Quasiexperimental, prospective, multicenter, single-group, and pretest/posttest methods were utilized to assess the quantitative data. The effectiveness of psychosocial interventions was assessed at baseline (visit 1) and after four follow-up visits. The following dimensions were assessed: mood state, discomfort, anxiety, degree of adjustment or adaptation to disease, and suffering. We also assessed the four dimensions of the spiritual pain scale: faith or spiritual beliefs, valuable faith or spiritual beliefs, meaning in life, and peace of mind/forgiveness. Qualitative analyses were performed via surveys to evaluate stakeholder satisfaction. We built 29 psychosocial support teams involving 133 professionals-mainly psychologists and social workers. During the study period, 8,964 patients and 11,810 family members attended. Significant improvements were observed in the psychosocial and spiritual dimensions assessed. Patients, family members, and stakeholders all showed high levels of satisfaction. This model of psychosocial care could serve as an example for other countries that wish to improve psychosocial and spiritual support. Our results confirm that specific psychosocial interventions delivered by well-trained experts can help to ease suffering and discomfort in end-of-life and palliative care patients, particularly those with high levels of pain or emotional distress.