Publications by authors named "Tamara Castillo Triviño"

25 Publications

  • Page 1 of 1

Gut Microbiota Changes in Experimental Autoimmune Encephalomyelitis and Cuprizone Mice Models.

ACS Chem Neurosci 2021 Feb 10. Epub 2021 Feb 10.

Multiple Sclerosis Group, Neuroscience Area, Biodonostia Research Institute, San Sebastian 20014, Spain.

Multiple sclerosis (MS) is a chronic and neurodegenerative disease of the central nervous system (CNS) characterized by the immune mediated attack on axons and the subsequent demyelination. There is growing evidence that the gut microbiota of MS patients is altered; however, the connection between demyelination events and changes in the gut microbiota has not been determined. The objective of the current work was to characterize the microbial dysbiosis in two murine demyelinating models and to study the correlation between them. Concurrently, their suitability as predictors of microbial changes in MS patients was assessed. To this purpose, experimental autoimmune encephalomyelitis (EAE) and cuprizone (CPZ) models were induced in C57BL/6 mice that were monitored for 4 and 9 weeks, respectively. Fecal samples were collected during disease progression. Motor skill performance was evaluated by EAE scale measurement in EAE mice and demyelination by magnetic resonance imaging (MRI) in CPZ ones. EAE and CPZ mice revealed drastic microbial changes according to disease progression, adding a new layer of complexity to the understanding of demyelination and remyelination processes. Besides, the reported microbial changes replicate most of the characteristics that define the potential dysbiosis in MS patients. The controlled environment and stable diet that animals have in research centers offer an exceptional scenario to modify animal's microbiota and provide opportunities to study host microbiota interplay with restrained conditions not achievable in human studies. Nevertheless the slight differences from murine model's and patient's microbiota should be considered in the design of studies aiming to modulate the microbiota.
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http://dx.doi.org/10.1021/acschemneuro.0c00695DOI Listing
February 2021

Determinants of therapeutic lag in multiple sclerosis.

Mult Scler 2021 Jan 11:1352458520981300. Epub 2021 Jan 11.

CORe, Department of Medicine, University of Melbourne, Melbourne, VIC, Australia/Melbourne MS Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia.

Background: A delayed onset of treatment effect, termed therapeutic lag, may influence the assessment of treatment response in some patient subgroups.

Objectives: The objective of this study is to explore the associations of patient and disease characteristics with therapeutic lag on relapses and disability accumulation.

Methods: Data from MSBase, a multinational multiple sclerosis (MS) registry, and OFSEP, the French MS registry, were used. Patients diagnosed with MS, minimum 1 year of exposure to MS treatment and 3 years of pre-treatment follow-up, were included in the analysis. Studied outcomes were incidence of relapses and disability accumulation. Therapeutic lag was calculated using an objective, validated method in subgroups stratified by patient and disease characteristics. Therapeutic lag under specific circumstances was then estimated in subgroups defined by combinations of clinical and demographic determinants.

Results: High baseline disability scores, annualised relapse rate (ARR) ⩾ 1 and male sex were associated with longer therapeutic lag on disability progression in sufficiently populated groups: females with expanded disability status scale (EDSS) < 6 and ARR < 1 had mean lag of 26.6 weeks (95% CI = 18.2-34.9), males with EDSS < 6 and ARR < 1 31.0 weeks (95% CI = 25.3-36.8), females with EDSS < 6 and ARR ⩾ 1 44.8 weeks (95% CI = 24.5-65.1), and females with EDSS ⩾ 6 and ARR < 1 54.3 weeks (95% CI = 47.2-61.5).

Conclusions: Pre-treatment EDSS and ARR are the most important determinants of therapeutic lag.
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http://dx.doi.org/10.1177/1352458520981300DOI Listing
January 2021

Whole-Transcriptome Analysis in Peripheral Blood Mononuclear Cells from Patients with Lipid-Specific Oligoclonal IgM Band Characterization Reveals Two Circular RNAs and Two Linear RNAs as Biomarkers of Highly Active Disease.

Biomedicines 2020 Nov 26;8(12). Epub 2020 Nov 26.

Biodonostia Health Research Institute, Neurosciences Area, Multiple Sclerosis Group, Doctor Begiristain, s/n, 20014 San Sebastian, Spain.

The presence of anti-myelin lipid-specific oligoclonal IgM bands (LS-OCMBs) has been defined as an accurate predictor of an aggressive evolution of multiple sclerosis. However, the detection of this biomarker is performed in cerebrospinal fluid, a quite invasive liquid biopsy. In the present study we aimed at studying the expression profile of miRNA, snoRNA, circRNA and linearRNA in peripheral blood mononuclear cells (PBMCs) from patients with lipid-specific oligoclonal IgM band characterization. We included a total of 89 MS patients, 47 with negative LS-OCMB status and 42 with positive status. Microarray (miRNA and snoRNA) and RNA-seq (circular and linear RNAs) were used to perform the profiling study in the discovery cohort and candidates were validated by RT-qPCR in the whole cohort. The biomarker potential of the candidates was evaluated by ROC curve analysis. RNA-seq and RT-qPCR validation revealed that two circular (hsa_circ_0000478 and hsa_circ_0116639) and two linear RNAs ( and ) are downregulated in PBMCs from patients with positive LS-OCMBs. Finally, those RNAs show a performance of a 70% accuracy in some of the combinations. The expression of hsa_circ_0000478, hsa_circ_0116639, and might serve as minimally invasive biomarkers of highly active disease.
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http://dx.doi.org/10.3390/biomedicines8120540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759842PMC
November 2020

RNA-Seq profiling of leukocytes reveals a sex-dependent global circular RNA upregulation in multiple sclerosis and 6 candidate biomarkers.

Hum Mol Genet 2020 Dec;29(20):3361-3372

Multiple Sclerosis Unit, Biodonostia Health Research Institute, San Sebastián 20014, Spain.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, with higher prevalence in women, that leads to neurological disability. The disease course and clinical phenotype are highly variable, and therefore, biomarkers for the diagnosis, classification, monitoring of the disease and treatment assessment are needed. Studies have shown a dysregulation in the coding and non-coding RNAs and proposed some as biomarkers. However, still none of them have reached the clinical practice. Recently, circular RNAs (circRNAs) have emerged as new players in the transcriptome that hold a great potential as biomarkers in several diseases. Leukocytes from 30 MS patients and 20 healthy controls (HCs) were RNA-sequenced to study the linear and circular transcriptome. Differential expression analysis was performed by DESeq, and circRNA candidates were studied in a second cohort (70 MS and 46 HC) by RT-qPCR and in paired samples drawn during the relapse and remission phases (20 patients). Among the differentially expressed circRNAs, 96.1% are upregulated in patients compared with controls, but similar circRNA profiles are found between MS types. The same upregulation trend was observed in females but not in males or in the linear transcriptome. The upregulation of 6 circRNAs was validated, and a change in their expression was found between relapse and remission. The 6 circRNAs showed a good performance to discriminate patients from HC with a combined area under the curve of 0.852. There is global, specific and sex-dependent increase of circRNA expression in MS, and 6 circRNAs are proposed as potential biomarkers.
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http://dx.doi.org/10.1093/hmg/ddaa219DOI Listing
December 2020

A New Risk Variant for Multiple Sclerosis at 11q23.3 Is Associated with Expansion of Circulating Regulatory T Cells.

J Clin Med 2020 Feb 26;9(3). Epub 2020 Feb 26.

Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat). Institut de Recerca Vall d'Hebron (VHIR). Hospital Universitari Vall d'Hebron. Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.

Genome-wide association studies and meta-analysis have contributed to the identification of more than 200 associated with multiple sclerosis (MS). However, a proportion of MS heritability remains unknown. We aimed to uncover new genetic variants associated with MS and determine their functional effects. For this, we resequenced the exons and regulatory sequences of 14 MS risk genes in a cohort of MS patients and healthy individuals ( = 1,070) and attempted to validate a selection of signals through genotyping in an independent cohort ( = 5,138). We identified three new MS-associated variants at C-X-C motif chemokine receptor 5 (, Ts translation elongation factor, mitochondrial ( and cytochrome P450 family 24 subfamily A member 1 (. Rs10892307 resulted in a new signal at the region that explains one of the associations with MS within the . This polymorphism and three others in high linkage disequilibrium mapped within regulatory regions. Of them, rs11602393 showed allele-dependent enhancer activity in the forward orientation as determined by luciferase reporter assays. Immunophenotyping using peripheral blood mononuclear cells from MS patients associated the minor allele of rs10892307 with increased percentage of regulatory T cells expressing CXCR5. This work reports a new signal for the MS risk and points to rs11602393 as the causal variant. The expansion of CXCR5+ circulating regulatory T cells induced by this variant could cause its MS association.
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http://dx.doi.org/10.3390/jcm9030625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141122PMC
February 2020

The Rare Signal Peptide Coding Variant rs28385692 Decreases Secretion of IL-22BP Isoform-1, -2 and -3 and Is Associated with Risk for Multiple Sclerosis.

Cells 2020 01 10;9(1). Epub 2020 Jan 10.

Neurogenomiks Laboratory, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain.

The locus is associated with risk for multiple sclerosis (MS) but causative variants are yet to be determined. In a single nucleotide polymorphism (SNP) screen of this locus in a Basque population, rs28385692, a rare coding variant substituting Leu for Pro at position 16 emerged significantly ( = 0.02). This variant is located in the signal peptide (SP) shared by the three secreted protein isoforms produced by (IL-22 binding protein-1(IL-22BPi1), IL-22BPi2 and IL-22BPi3). Genotyping was extended to a Europe-wide case-control dataset and yielded high significance in the full dataset ( = 3.17 × 10). Importantly, logistic regression analyses conditioning on the main known MS-associated SNP at this locus, rs17066096, revealed that this association was independent from the primary association signal in the full case-control dataset. In silico analysis predicted both disruption of the alpha helix of the H-region of the SP and decreased hydrophobicity of this region, ultimately affecting the SP cleavage site. We tested the effect of the p.Leu16Pro variant on the secretion of IL-22BPi1, IL-22BPi2 and IL-22BPi3 and observed that the Pro16 risk allele significantly lowers secretion levels of each of the isoforms to around 50%-60% in comparison to the Leu16 reference allele. Thus, our study suggests that genetically coded decreased levels of IL-22BP isoforms are associated with augmented risk for MS.
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http://dx.doi.org/10.3390/cells9010175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017210PMC
January 2020

ABO blood group distributions in multiple sclerosis patients from Basque Country; O as a protective factor.

Mult Scler J Exp Transl Clin 2019 Oct-Dec;5(4):2055217319888957. Epub 2019 Nov 15.

Multiple sclerosis Group, Biodonostia Health Research Institute, Spain.

Background: The relation between ABO/Rh groups and multiple sclerosis (MS) has been proposed in several studies, however there is a controversy about the role of these groups in the disease. Although it has been reported that some groups can be protective or risk factors, there is no consensus and discordant reports can be found in the literature.

Objectives And Methodology: In this short report, we analyze the ABO/Rh distribution in a MS cohort of 265 patients and compare these frequencies with the results obtained from the Basque Blood Donors bank (17,796 individuals) of the same region.

Results And Conclusions: From our data, the absence of immune antigens (A, B or Rhesus +) defined by the group O- seems to be protective in the MS group with an odds ratio of 0.49 (95% confidence interval 0.309-0.796), while the presence of Rh+ plus A or B seems to be a risk in developing multiple sclerosis.
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http://dx.doi.org/10.1177/2055217319888957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859684PMC
November 2019

Multi-centre validation of a flow cytometry method to identify optimal responders to interferon-beta in multiple sclerosis.

Clin Chim Acta 2019 Jan 5;488:135-142. Epub 2018 Nov 5.

Immunology Dpt. and Biostatistic Unit, Hospital Universitario Ramón y Cajal, IRYCIS, Ctra. de Colmenar Viejo km 9.100, 28034 Madrid, Spain; Red Española de Esclerosis Múltiple (REEM), Spain. Electronic address:

Background And Objectives: Percentages of blood CD19+CD5+ B cells and CD8+perforin+ T lymphocytes can predict response to Interferon (IFN)-beta treatment in relapsing-remitting multiple sclerosis (RRMS) patients. We aimed to standardize their detection in a multicenter study, prior to their implementation in clinical practice.

Methods: Fourteen hospitals participated in the study. A reference centre was established for comparison studies. Peripheral blood cells of 105 untreated RRMS patients were studied. Every sample was analyzed in duplicate in the participating centre and in the reference one by flow cytometry. When needed, participating centres corrected fluorescence compensations and negative cut-off position following reference centre suggestions. Concordance between results obtained by participating centres and by reference one was evaluated by intraclass correlation coefficients (ICC) and Spearman correlation test. Centre performance was measured by using z-scores values.

Results: After results review and corrective actions implementation, overall ICC was 0.86 (CI: 0.81-0.91) for CD19+CD5+ B cell and 0.89 (CI: 0.85-0.93) for CD8+ perforin+ T cell quantification; Spearman r was 0.92 (0.89-0.95; p <0.0001) and 0.92 (0.88-0.95; p <0.0001) respectively. All centres obtained z-scores≤0.5 for both biomarkers.

Conclusion: Homogenous percentages of CD19+CD5+ B cells and CD8 perforin+ T lymphocytes can be obtained if suitable compensation values and negative cut-off are pre-established.
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http://dx.doi.org/10.1016/j.cca.2018.11.008DOI Listing
January 2019

The First Dose of Fingolimod Affects Circulating Extracellular Vesicles in Multiple Sclerosis Patients.

Int J Mol Sci 2018 Aug 19;19(8). Epub 2018 Aug 19.

Multiple Sclerosis Unit, Biodonostia Health Research Institute-Donostia University Hospital, 20014 San Sebastian, Spain.

Extracellular vesicles (EVs) are membrane-bound particles involved in intercellular communication. They carry proteins, lipids, and nucleotides such as microRNAs (miRNAs) from the secreting cell that can modulate target cells. We and others have previously described the presence of EVs in peripheral blood of multiple sclerosis (MS) patients and postulated them as novel biomarkers. However, their immune function in MS pathogenesis and the effect during the onset of new immunomodulatory therapies on EVs remain elusive. Here, we isolated plasma EVs from fingolimod-treated MS patients in order to assess whether EVs are affected by the first dose of the treatment. We quantified EVs, analyzed their miRNA cargo, and checked their immune regulatory function. Results showed an elevated EV concentration with a dramatic change in their miRNA cargo 5 h after the first dose of fingolimod. Besides, EVs obtained prior to fingolimod treatment showed an increased immune regulatory activity compared to EVs obtained 5 h post-treatment. This work suggests that EVs are implicated in the mechanism of action of immunomodulatory treatments from the initial hours and opens a new avenue to explore a potential use of EVs for early treatment monitoring.
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http://dx.doi.org/10.3390/ijms19082448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121302PMC
August 2018

Circular RNA profiling reveals that circular RNAs from ANXA2 can be used as new biomarkers for multiple sclerosis.

Hum Mol Genet 2017 09;26(18):3564-3572

Multiple Sclerosis Unit, Neurosciences Area, Biodonostia Health Research Institute, 20014, San Sebastián, Spain.

Multiple sclerosis is an autoimmune disease, with higher prevalence in women, in whom the immune system is dysregulated. This dysregulation has been shown to correlate with changes in transcriptome expression as well as in gene-expression regulators, such as non-coding RNAs (e.g. microRNAs). Indeed, some of these have been suggested as biomarkers for multiple sclerosis even though few biomarkers have reached the clinical practice. Recently, a novel family of non-coding RNAs, circular RNAs, has emerged as a new player in the complex network of gene-expression regulation. MicroRNA regulation function through a 'sponge system' and a RNA splicing regulation function have been proposed for the circular RNAs. This regulating role together with their high stability in biofluids makes them seemingly good candidates as biomarkers. Given the dysregulation of both protein-coding and non-coding transcriptome that have been reported in multiple sclerosis patients, we hypothesised that circular RNA expression may also be altered. Therefore, we carried out expression profiling of 13.617 circular RNAs in peripheral blood leucocytes from multiple sclerosis patients and healthy controls finding 406 differentially expressed (P-value < 0.05, Fold change > 1.5) and demonstrate after validation that, circ_0005402 and circ_0035560 are underexpressed in multiple sclerosis patients and could be used as biomarkers of the disease.
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http://dx.doi.org/10.1093/hmg/ddx243DOI Listing
September 2017

SncRNA (microRNA &snoRNA) opposite expression pattern found in multiple sclerosis relapse and remission is sex dependent.

Sci Rep 2016 Feb 1;6:20126. Epub 2016 Feb 1.

Biodonostia Institute, Neuroscience Area, Multiple Sclerosis Group, San Sebastian, Spain.

Multiple sclerosis (MS) is a common inflammatory and degenerative disease that causes neurological disability. It affects young adults and its prevalence is higher in women. The most common form is manifested as a series of acute episodes of neurological disability (relapses) followed by a recovery phase (remission). Recently, non-coding RNAs have emerged as new players in transcriptome regulation, and in turn, they could have a significant role in MS pathogenesis. In this context, our aim was to investigate the involvement of microRNAs and snoRNAs in the relapse-remission dynamics of MS in peripheral blood leucocytes, to shed light on the molecular and regulatory mechanisms that underlie this complex process. With this approach, we found that a subset of small non-coding RNAs (sncRNA) is altered in relapse and remission, revealing unexpected opposite changes that are sex dependent. Furthermore, we found that a relapse-related miRNA signature regulated general metabolism processes in leucocytes, and miRNA altered in remission are involved in the regulation of innate immunity. We observed that sncRNA dysregulation is different in relapse and remission leading to differences in transcriptome regulation, and that this process is sex dependent. In conclusion, relapse and remission have a different molecular background in men and women.
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http://dx.doi.org/10.1038/srep20126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4735588PMC
February 2016

DAT imaging and clinical biomarkers in relatives at genetic risk for LRRK2 R1441G Parkinson's disease.

Mov Disord 2016 Mar 21;31(3):335-43. Epub 2015 Dec 21.

Neurology Service, Hospital Universitario Donostia, San Sebastian, Spain.

Background: The objective of this study was to study motor and nonmotor symptoms and striatal dopaminergic denervation, as well as the relationship between them, in a cohort of asymptomatic relatives of patients with Parkinson's disease (PD) with the R1441G-leucine-rich repeat kinase 2 mutation.

Methods: Asymptomatic relatives of patients with PD and this mutation were tested for the presence of the mutation and evaluated for striatal, putamenal, and caudate dopaminergic transporters using (123)I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane single-photon emission computed tomography binding ratios. Clinical and neuropsychological evaluations including timed motor tests, a smell identification test, and global cognition, attention, executive, visuospatial, and memory functions as well as depression, constipation, and rapid eye movement sleep behavior disorder were also assessed.

Results: Twenty-seven carriers and 19 noncarriers were studied. Compared with noncarriers, mutation carriers had significantly lower (123)I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropan mean striatal (P = 0.03), mean putamenal (P = 0.01), and lowest putamenal (P = 0.01) binding ratios. Multiple linear regression analysis showed that the carrier status and the execution of timed tests significantly predicted striatal (123)I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane binding. The proportion of variation accounted for by the regression model of these variables was 69% for the putamen and 53% for the caudate nucleus.

Conclusions: Asymptomatic carriers of the R1441G-leucine-rich repeat kinase 2 mutation have evidence of dopaminergic nigrostriatal denervation, mainly in the putamen, which is associated with a decline in the execution of complex motor tests. These tests could be early indicators of the ongoing dopaminergic deficit in this group at risk of PD.
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http://dx.doi.org/10.1002/mds.26478DOI Listing
March 2016

Age gene expression and coexpression progressive signatures in peripheral blood leukocytes.

Exp Gerontol 2015 Dec 8;72:50-6. Epub 2015 Sep 8.

Multiple Sclerosis and Neuromuscular Diseases Groups, Neurosciences Area, Biodonostia Health Research Institute, Donostia/San Sebastián, Spain; Neurology Department, Donostia University Hospital, Donostia/San Sebastián, Spain. Electronic address:

Both cellular senescence and organismic aging are known to be dynamic processes that start early in life and progress constantly during the whole life of the individual. In this work, with the objective of identifying signatures of age-related progressive change at the transcriptomic level, we have performed a whole-genome gene expression analysis of peripheral blood leukocytes in a group of healthy individuals with ages ranging from 14 to 93 years. A set of genes with progressively changing gene expression (either increase or decrease with age) has been identified and contextualized in a coexpression network. A modularity analysis has been performed on this network and biological-term and pathway enrichment analyses have been used for biological interpretation of each module. In summary, the results of the present work reveal the existence of a transcriptomic component that shows progressive expression changes associated to age in peripheral blood leukocytes, highlighting both the dynamic nature of the process and the need to complement young vs. elder studies with longitudinal studies that include middle aged individuals. From the transcriptional point of view, immunosenescence seems to be occurring from a relatively early age, at least from the late 20s/early 30s, and the 49-56 year old age-range appears to be critical. In general, the genes that, according to our results, show progressive expression changes with aging are involved in pathogenic/cellular processes that have classically been linked to aging in humans: cancer, immune processes and cellular growth vs. maintenance.
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http://dx.doi.org/10.1016/j.exger.2015.09.003DOI Listing
December 2015

Identification of ncRNAs as potential therapeutic targets in multiple sclerosis through differential ncRNA - mRNA network analysis.

BMC Genomics 2015 Mar 28;16:250. Epub 2015 Mar 28.

Multiple Sclerosis group, Biodonostia Health Research Institute, Paseo Dr. Begiristain s/n, San Sebastián, 20001, Spain.

Background: Several studies have revealed a potential role for both small nucleolar RNAs (snoRNAs) and microRNAs (miRNAs) in the physiopathology of relapsing-remitting multiple sclerosis (RRMS). This potential implication has been mainly described through differential expression studies. However, it has been suggested that, in order to extract additional information from large-scale expression experiments, differential expression studies must be complemented with differential network studies. Thus, the present work is aimed at the identification of potential therapeutic ncRNA targets for RRMS through differential network analysis of ncRNA - mRNA coexpression networks. ncRNA - mRNA coexpression networks have been constructed from both selected ncRNA (specifically miRNAs, snoRNAs and sdRNAs) and mRNA large-scale expression data obtained from 22 patients in relapse, the same 22 patients in remission and 22 healthy controls. Condition-specific (relapse, remission and healthy) networks have been built and compared to identify the parts of the system most affected by perturbation and aid the identification of potential therapeutic targets among the ncRNAs.

Results: All the coexpression networks we built present a scale-free topology and many snoRNAs are shown to have a prominent role in their architecture. The differential network analysis (relapse vs. remission vs. controls' networks) has revealed that, although both network topology and the majority of the genes are maintained, few ncRNA - mRNA links appear in more than one network. We have selected as potential therapeutic targets the ncRNAs that appear in the disease-specific network and were found to be differentially expressed in a previous study.

Conclusions: Our results suggest that the diseased state of RRMS has a strong impact on the ncRNA - mRNA network of peripheral blood leukocytes, as a massive rewiring of the network happens between conditions. Our findings also indicate that the role snoRNAs have in targeted gene silencing is a widespread phenomenon. Finally, among the potential therapeutic target ncRNAs, SNORA40 seems to be the most promising candidate.
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http://dx.doi.org/10.1186/s12864-015-1396-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4391585PMC
March 2015

Ventricular tachycardia on chronic fingolimod treatment for multiple sclerosis.

J Neurol Neurosurg Psychiatry 2015 Aug 2;86(8):931-2. Epub 2015 Apr 2.

Multiple Sclerosis Unit, Department of Neurology, Donostia University Hospital, San Sebastian, Spain Department of Neuroscience Area, Biodonostia Research Institute, San Sebastian, Spain.

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http://dx.doi.org/10.1136/jnnp-2014-310013DOI Listing
August 2015

[Smoking and multiple sclerosis].

Rev Neurol 2015 Feb;60(4):169-78

Hospital Universitario Donostia, San Sebastian, Espana.

Introduction: Multiple sclerosis (MS) is a complex autoimmune disease of unknown etiology, in which genetic and environmental factors interact and determine the disease susceptibility. In recent years, smoking effect has been one of the emerging environmental factors in the study of MS and has been associated with an increased susceptibility and an increase in disease progression.

Aim: To review the current evidence on the role of smoking in MS.

Development: The review includes an update of studies that have analyzed different aspects of tobacco in MS, including the potential pathogenic pathways involved, association of smoking and risk of MS, interactions with other risk factors and the effect of smoking in the disease course.

Conclusions: Observational studies show that smoking significantly increases the risk of MS (odds ratio~1.5) and is an independent risk factor. However, MS is a complex disease and this risk may be modified depending on the interaction with other genetic and environmental factors. The role of smoking as a progression factor is more controversial, with confronted results and highly variable studies, making it difficult to draw any conclusion. The mechanisms by which smoking may modify the risk and progression of the disease have to be further investigated.
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February 2015

Circulating microparticles reflect treatment effects and clinical status in multiple sclerosis.

Biomark Med 2014 ;8(5):653-61

Multiple Sclerosis Unit, Neuroscience Area, Biodonostia Health Research Institute, San Sebastián, Spain.

Aim: To evaluate whether circulating microparticles (MPs) derived from three cell subtypes (platelets, total leukocytes or monocytes) obtained from multiple sclerosis (MS) patients were modulated depending on the clinical status and to investigate the effect of treatments on MP levels.

Patients & Methods: The MP counts were assessed with flow cytometry.

Results: The platelet-derived MP level was higher in untreated MS patients than controls. Relapsing-remitting patients showed the highest levels in the three subtypes of MP while secondary progressive patients presented similar levels to those of healthy controls. Treatments had significant effects increasing the three subtypes of MP counts.

Conclusion: We suggest that MPs play a role in MS pathogenesis, reflecting disease status with an increment of their shedding during inflammatory periods and turning to baseline during chronic progressive degeneration.
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http://dx.doi.org/10.2217/bmm.14.9DOI Listing
August 2015

[Cognitive performance and quality of life in multiple sclerosis in Gipuzkoa].

Rev Neurol 2014 Apr;58(8):337-44

Universidad del Pais Vasco, Leioa, Espana.

Introduction: Cognitive impairment and the presence of depressive symptoms, which are commonly found in patients with multiple sclerosis, affect the patients' quality of life. AIM. To describe the quality of life, cognitive compromise and levels of depression, in relation to other clinical variables, in patients with multiple sclerosis in the province of Gipuzkoa.

Patients And Methods: A total of 114 patients were submitted to neuropsychological evaluation. The MSQoL-54 and Beck's Depression Inventory were applied to evaluate the quality of life and levels of depression. Three main analyses were performed: a comparison of cognitive performance among subtypes, an analysis of the correlation among clinical, neuro-psychological and quality of life variables, and an analysis of the effects of gender on cognitive performance.

Results: A neuropsychological pattern is found in multiple sclerosis that is characterised by a slowing of the processing of information and attentional difficulties. Quality of life is related with depressive syndromes and with overall cognitive performance but not with clinical factors such as the rate of attacks or the length of time the disease lasts. The data confirm the existence of poorer cognitive performance in males, above all in terms of verbal auditory memory.

Conclusions: Gender is presented as a factor that modulates the impact of the disease on cognitive performance, which reinforces the interest in conducting studies that clarify the origin of such differences. Furthermore, the quality of life displays a greater relationship with the degree of adaptation to the disease than with its symptoms.
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April 2014

Transcriptomic profile reveals gender-specific molecular mechanisms driving multiple sclerosis progression.

PLoS One 2014 28;9(2):e90482. Epub 2014 Feb 28.

Multiple Sclerosis Unit, Neuroscience Area, Biodonostia Health Research Institute, Donostia-San Sebastian, Spain ; Spanish Multiple Sclerosis Net (REEM), Barcelona, Spain.

Background: Although the most common clinical presentation of multiple sclerosis (MS) is the so called Relapsing-Remitting MS (RRMS), the molecular mechanisms responsible for its progression are currently unknown. To tackle this problem, a whole-genome gene expression analysis has been performed on RRMS patients.

Results: The comparative analysis of the Affymetrix Human Gene 1.0 ST microarray data from peripheral blood leucocytes obtained from 25 patients in remission and relapse and 25 healthy subjects has revealed 174 genes altered in both remission and relapse, a high proportion of them showing what we have called "mirror pattern": they are upregulated in remission and downregulated in relapse or vice versa. The coexpression analysis of these genes has shown that they are organized in three female-specific and one male-specific modules.

Conclusions: The interpretation of the modules of the coexpression network suggests that Epstein-Barr virus (EBV) reactivation of B cells happens in MS relapses; however, qPCR expression data of the viral genes supports that hypothesis only in female patients, reinforcing the notion that different molecular processes drive disease progression in females and males. Besides, we propose that the "primed" state showed by neutrophils in women is an endogenous control mechanism triggered to keep EBV reactivation under control through vitamin B12 physiology. Finally, our results also point towards an important sex-specific role of non-coding RNA in MS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0090482PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3938749PMC
June 2015

Rituximab in relapsing and progressive forms of multiple sclerosis: a systematic review.

PLoS One 2013 2;8(7):e66308. Epub 2013 Jul 2.

Multiple Sclerosis Center, Department of Neurology, University of California San Francisco, San Francisco, California, USA.

Background: Rituximab is an anti-CD20 monoclonal antibody approved for non Hodgkin lymphoma and rheumatoid arthritis. It is being considered for the treatment of MS.

Objectives: To evaluate the efficacy and safety of rituximab for MS treatment.

Data Collection: Studies were selected if they were clinical trials, irrespective of the dosage or combination therapies.

Main Results: Four studies with a total of 599 patients were included. One assessed the efficacy of rituximab for primary progressive (PP) MS while the other three focused on relapsing-remitting (RR) MS. In the PPMS study, rituximab delayed time to confirmed disease progression (CDP) in pre-planned sub-group analyses. The increase in T2 lesion volume was lower in the rituximab group at week 96 compared with placebo. For the RRMS studies, an open-label phase I study found that rituximab reduced the annualized relapse rate to 0.25 from pre-therapy baseline to week 24, while in the randomized placebo-controlled phase II trial, annualized relapse rates were 0.37 in the rituximab group and 0.84 in the placebo group (p = 0.04) at week 24. Rituximab dramatically reduced the number of gadolinium-enhancing lesions on brain MRI scans for both RRMS studies. Off-label rituximab as an add-on therapy in patients with breakthrough disease on first-line agents was associated with an 88% reduction when comparing the mean number of gadolinium-enhancing lesions prior to and after the treatment. Although frequent adverse events classified as mild or moderate occurred in up to 77% of the patients, there were no grade 4 infusion-related adverse events. AUTHOR’S CONCLUSION: Despite the frequent mild/moderate adverse events related to the drug, rituximab appears overall safe for up to 2 years of therapy and has a substantial impact on the inflammatory disease activity (clinical and/or radiological) of RRMS. The effect of rituximab on disease progression in PPMS appears to be marginal.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0066308PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699597PMC
January 2014

Clinical response to thalidomide in the treatment of intracranial tuberculomas: case report.

Clin Neuropharmacol 2013 Mar-Apr;36(2):70-2

Department of Neurology, Universitary Hospital of Donostia, San Sebastian, Spain.

We describe a patient with multiple intracranial tuberculomas resistant to standard care with antituberculosis drugs and corticosteroids who responded well to thalidomide. Adjunctive thalidomide may have a role in the management of refractory intracranial tuberculomas, although it should be used conservatively owing to its potential adverse events.
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http://dx.doi.org/10.1097/WNF.0b013e318285caa1DOI Listing
December 2013

HLA-DRB1*15:01 and multiple sclerosis: a female association?

Mult Scler 2012 May 29;18(5):569-77. Epub 2011 Nov 29.

Multiple Sclerosis Unit, Neuroscience Area, Biodonostia Health Research Institute, Donostia-San Sebastian, Spain.

Background: The association between multiple sclerosis (MS) and the HLA-DRB1*15:01 haplotype has been proven to be strong, but its molecular basis remains unclear. Vitamin D receptor (VDR) gene variants and sex have been proposed to modulate this association.

Objectives: 1) Test the association of MS with *15:01 and VDR variants; 2) check whether VDR variants and/or sex modulate the risk conferred by *15:01; 3) study whether *15:01, VDR variants and/or sex affect HLA II gene expression.

Methods: Peripheral blood from 364 MS patients and 513 healthy controls was obtained and DNA and total RNA were extracted from leukocytes. HLA-DRB1, DRB5 and DQA1 gene expression measurements and *15:01 genotyping were performed by qPCR. VDR variants were genotyped by PCR-RFLP.

Results: Our data confirms that the *15:01 haplotype confers a higher risk of suffering from MS (OR = 1.364; 95% CI = 1.107-1.681). No association was found between VDR variants and MS, but they were shown to moderately modulate the risk conferred by *15:01. Sex confers a much stronger modulation and the *15:01-MS association seems to be female specific. A higher *15:01 frequency has been observed in Basques (45.1%). *15:01 positive samples showed a significant overexpression of DRB1 (p < 0.001), DRB5 (p < 0.001) and DQA1 (p = 0.004) in patients. DRB1 (p = 0.004) and DRB5 (p < 0.001) were also overexpressed in *15:01 controls.

Conclusions: We confirm the *15:01-MS association and support that it is female specific. The relevance of ethnic origin on association studies has also been highlighted. HLA-DRB1*15:01 seems to be a haplotype consistently linked to high HLA II gene expression.
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http://dx.doi.org/10.1177/1352458511426813DOI Listing
May 2012

Switching multiple sclerosis patients with breakthrough disease to second-line therapy.

PLoS One 2011 Feb 3;6(2):e16664. Epub 2011 Feb 3.

Multiple Sclerosis Center, Department of Neurology, University of California San Francisco, San Francisco, California, USA.

Background: Multiple sclerosis (MS) patients with breakthrough disease on immunomodulatory drugs are frequently offered to switch to natalizumab or immunosuppressants. The effect of natalizumab monotherapy in patients with breakthrough disease is unknown.

Methods: This is an open-label retrospective cohort study of 993 patients seen at least four times at the University of California San Francisco MS Center, 95 had breakthrough disease on first-line therapy (60 patients switched to natalizumab, 22 to immunosuppressants and 13 declined the switch [non-switchers]). We used Poisson regression adjusted for potential confounders to compare the relapse rate within and across groups before and after the switch.

Results: In the within-group analyses, the relapse rate decreased by 70% (95% CI 50,82%; p<0.001) in switchers to natalizumab and by 77% (95% CI 59,87%; p<0.001) in switchers to immunosuppressants; relapse rate in non-switchers did not decrease (6%, p =  0.87). Relative to the reduction among non-switchers, the relapse rate was reduced by 68% among natalizumab switchers (95% CI 19,87%; p = 0.017) and by 76% among the immunosuppressant switchers (95% CI 36,91%; p = 0.004).

Conclusions: Switching to natalizumab or immunosuppressants in patients with breakthrough disease is effective in reducing clinical activity of relapsing MS. The magnitude of the effect and the risk-benefit ratio should be evaluated in randomized clinical trials and prospective cohort studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0016664PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033401PMC
February 2011

Differential micro RNA expression in PBMC from multiple sclerosis patients.

PLoS One 2009 Jul 20;4(7):e6309. Epub 2009 Jul 20.

Multiple Sclerosis Unit, Biodonostia Institute, San Sebastián, Spain.

Differences in gene expression patterns have been documented not only in Multiple Sclerosis patients versus healthy controls but also in the relapse of the disease. Recently a new gene expression modulator has been identified: the microRNA or miRNA. The aim of this work is to analyze the possible role of miRNAs in multiple sclerosis, focusing on the relapse stage. We have analyzed the expression patterns of 364 miRNAs in PBMC obtained from multiple sclerosis patients in relapse status, in remission status and healthy controls. The expression patterns of the miRNAs with significantly different expression were validated in an independent set of samples. In order to determine the effect of the miRNAs, the expression of some predicted target genes of these were studied by qPCR. Gene interaction networks were constructed in order to obtain a co-expression and multivariate view of the experimental data. The data analysis and later validation reveal that two miRNAs (hsa-miR-18b and hsa-miR-599) may be relevant at the time of relapse and that another miRNA (hsa-miR-96) may be involved in remission. The genes targeted by hsa-miR-96 are involved in immunological pathways as Interleukin signaling and in other pathways as wnt signaling. This work highlights the importance of miRNA expression in the molecular mechanisms implicated in the disease. Moreover, the proposed involvement of these small molecules in multiple sclerosis opens up a new therapeutic approach to explore and highlight some candidate biomarker targets in MS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0006309PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2708922PMC
July 2009