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Find video protocols related to scientific articles indexed in Pubmed.
Human endogenous retrovirus HERV-Fc1 association with multiple sclerosis susceptibility: a meta-analysis.
PLoS ONE
PUBLISHED: 01-01-2014
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Human endogenous retroviruses (HERVs) are repetitive sequences derived from ancestral germ-line infections by exogenous retroviruses and different HERV families have been integrated in the genome. HERV-Fc1 in chromosome X has been previously associated with multiple sclerosis (MS) in Northern European populations. Additionally, HERV-Fc1 RNA levels of expression have been found increased in plasma of MS patients with active disease. Considering the North-South latitude gradient in MS prevalence, we aimed to evaluate the role of HERV-Fc1on MS risk in three independent Spanish cohorts.
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MANBA, CXCR5, SOX8, RPS6KB1 and ZBTB46 are genetic risk loci for multiple sclerosis.
Brain
PUBLISHED: 06-07-2013
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A recent genome-wide association study reported five loci for which there was strong, but sub-genome-wide significant evidence for association with multiple sclerosis risk. The aim of this study was to evaluate the role of these potential risk loci in a large and independent data set of ? 20,000 subjects. We tested five single nucleotide polymorphisms rs228614 (MANBA), rs630923 (CXCR5), rs2744148 (SOX8), rs180515 (RPS6KB1), and rs6062314 (ZBTB46) for association with multiple sclerosis risk in a total of 8499 cases with multiple sclerosis, 8765 unrelated control subjects and 958 trios of European descent. In addition, we assessed the overall evidence for association by combining these newly generated data with the results from the original genome-wide association study by meta-analysis. All five tested single nucleotide polymorphisms showed consistent and statistically significant evidence for association with multiple sclerosis in our validation data sets (rs228614: odds ratio = 0.91, P = 2.4 × 10(-6); rs630923: odds ratio = 0.89, P = 1.2 × 10(-4); rs2744148: odds ratio = 1.14, P = 1.8 × 10(-6); rs180515: odds ratio = 1.12, P = 5.2 × 10(-7); rs6062314: odds ratio = 0.90, P = 4.3 × 10(-3)). Combining our data with results from the previous genome-wide association study by meta-analysis, the evidence for association was strengthened further, surpassing the threshold for genome-wide significance (P < 5 × 10(-8)) in each case. Our study provides compelling evidence that these five loci are genuine multiple sclerosis susceptibility loci. These results may eventually lead to a better understanding of the underlying disease pathophysiology.
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TNFRSF1A polymorphisms rs1800693 and rs4149584 in patients with multiple sclerosis.
Neurology
PUBLISHED: 04-26-2013
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To investigate the roles of 2 polymorphisms of the tumor necrosis factor (TNF) receptor superfamily member 1A (TNFRSF1A) gene, rs1800693 (a common variant) and rs4149584 (a coding polymorphism that results in an amino acid substitution-R92Q), as genetic modifiers of multiple sclerosis (MS), and to evaluate their potential functional implications in the disease.
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Oxidative stress and proinflammatory cytokines contribute to demyelination and axonal damage in a cerebellar culture model of neuroinflammation.
PLoS ONE
PUBLISHED: 02-19-2013
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Demyelination and axonal damage are critical processes in the pathogenesis of multiple sclerosis (MS). Oxidative stress and pro-inflammatory cytokines elicited by inflammation mediates tissue damage.
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A trifluoromethyl analogue of celecoxib exerts beneficial effects in neuroinflammation.
PLoS ONE
PUBLISHED: 01-01-2013
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Celecoxib is a selective cyclooxygenase-2 (COX2) inhibitor. We have previously shown that celecoxib inhibits experimental autoimmune encephalomyelitis (EAE) in COX-2-deficient mice, suggestive for a mode of action involving COX2-independent pathways. In the present study, we tested the effect of a trifluoromethyl analogue of celecoxib (TFM-C) with 205-fold lower COX-2 inhibitory activity in two models of neuroinflammation, i.e. cerebellar organotypic cultures challenged with LPS and the EAE mouse model for multiple sclerosis. TFM-C inhibited secretion of IL-1?, IL-12 and IL-17, enhanced that of TNF-? and RANTES, reduced neuronal axonal damage and protected from oxidative stress in the organotypic model. TFM-C blocked TNF-? release in microglial cells through a process involving intracellular retention, but induced TNF-? secretion in primary astrocyte cultures. Finally, we demonstrate that TFM-C and celecoxib ameliorated EAE with equal potency. This coincided with reduced secretion of IL-17 and IFN-? by MOG-reactive T-cells and of IL-23 and inflammatory cytokines by bone marrow-derived dendritic cells. Our study reveals that non-coxib analogues of celecoxib may have translational value in the treatment of neuro-inflammatory conditions.
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Fine mapping and functional analysis of the multiple sclerosis risk gene CD6.
PLoS ONE
PUBLISHED: 01-01-2013
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CD6 has recently been identified and validated as risk gene for multiple sclerosis (MS), based on the association of a single nucleotide polymorphism (SNP), rs17824933, located in intron 1. CD6 is a cell surface scavenger receptor involved in T-cell activation and proliferation, as well as in thymocyte differentiation. In this study, we performed a haptag SNP screen of the CD6 gene locus using a total of thirteen tagging SNPs, of which three were non-synonymous SNPs, and replicated the recently reported GWAS SNP rs650258 in a Spanish-Basque collection of 814 controls and 823 cases. Validation of the six most strongly associated SNPs was performed in an independent collection of 2265 MS patients and 2600 healthy controls. We identified association of haplotypes composed of two non-synonymous SNPs [rs11230563 (R225W) and rs2074225 (A257V)] in the 2(nd) SRCR domain with susceptibility to MS (P max(T) permutation?=?1×10(-4)). The effect of these haplotypes on CD6 surface expression and cytokine secretion was also tested. The analysis showed significantly different CD6 expression patterns in the distinct cell subsets, i.e. - CD4(+) naïve cells, P?=?0.0001; CD8(+) naïve cells, P<0.0001; CD4(+) and CD8(+) central memory cells, P?=?0.01 and 0.05, respectively; and natural killer T (NKT) cells, P?=?0.02; with the protective haplotype (RA) showing higher expression of CD6. However, no significant changes were observed in natural killer (NK) cells, effector memory and terminally differentiated effector memory T cells. Our findings reveal that this new MS-associated CD6 risk haplotype significantly modifies expression of CD6 on CD4(+) and CD8(+) T cells.
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Cytokine gene polymorphisms and human autoimmune disease in the era of genome-wide association studies.
J. Interferon Cytokine Res.
PUBLISHED: 12-22-2011
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Cytokine (receptor) genes have traditionally attracted great interest as plausible genetic risk factors for autoimmune disease. Since 2007, the implementation of genome-wide association studies has facilitated the robust identification of allelic variants in more than 35 cytokine loci as susceptibility factors for a wide variety of over 15 autoimmune disorders. In this review, we catalog the gene loci of interleukin, chemokine, and tumor necrosis factor receptor superfamily and ligands that have emerged as autoimmune risk factors. We examine recent progress made in the clarification of the functional mechanisms by which polymorphisms in the genes coding for interleukin-2 receptor alpha (IL2RA), IL7R, and IL23R may alter risk for autoimmune disease, and discuss opposite autoimmune risk alleles found, among others, at the IL10 locus.
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Allelic combinations of immune-response genes associated with glatiramer acetate treatment response in Russian multiple sclerosis patients.
Pharmacogenomics
PUBLISHED: 11-23-2011
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Glatiramer acetate (GA) is widely used as a first-line disease-modifying treatment for multiple sclerosis (MS). However, a significant proportion of MS patient appears to experience modest benefit from GA-treatment. Genetic variants affecting the clinical response to GA are believed to be relevant as biomarkers of GA-treatment efficiency.
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The endoplasmic reticulum protein folding factory and its chaperones: new targets for drug discovery?
Br. J. Pharmacol.
PUBLISHED: 06-30-2011
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Cytosolic heat shock proteins have received significant attention as emerging therapeutic targets. Much of this excitement has been triggered by the discovery that HSP90 plays a central role in the maintenance and stability of multifarious oncogenic membrane receptors and their resultant tyrosine kinase activity. Numerous studies have dealt with the effects of small molecules on chaperone- and stress-related pathways of the endoplasmic reticulum (ER). However, unlike cytosolic chaperones, relatively little emphasis has been placed upon translational avenues towards targeting of the ER for inhibition of folding/secretion of disease-promoting proteins. Here, we summarise existing small molecule inhibitors and potential future targets of ER chaperone-mediated inhibition. Client proteins of translational relevance in disease treatment are outlined, alongside putative future disease treatment modalities based on ER-centric targeted therapies. Particular attention is paid to cancer and autoimmune disorders via the effects of the GRP94 inhibitor geldanamycin and its population of client proteins, overloading of the unfolded protein response, and inhibition of members of the IL-12 family of cytokines by celecoxib and non-coxib analogues.
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Pharmacogenomics and multiple sclerosis: moving toward individualized medicine.
Curr Neurol Neurosci Rep
PUBLISHED: 06-25-2011
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Notwithstanding the availability of disease-modifying treatments including interferon-?, glatiramer acetate, and natalizumab, a considerable proportion of multiple sclerosis (MS) patients experience continued progression of disease, clinical relapses, disease activity on MRI, and adverse effects. Application of gene expression, proteomic or genomic approaches is universally accepted as a suitable strategy toward the identification of biomarkers with predictive value for beneficial/poor clinical response to therapy and treatment risks. This review focuses on recent progress in research on the pharmacogenomics of disease-modifying therapies for MS. Although MS drug response biomarkers are not yet routinely implemented in the clinic, the diversity of reported, promising molecular markers is rapidly increasing. Even though most of these markers await further validation, given time, this research is likely to empower neurologists with an enhanced armamentarium to facilitate rational decisions on therapy and patient management.
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Single-nucleotide polymorphisms in response to interferon-beta therapy in multiple sclerosis.
J. Interferon Cytokine Res.
PUBLISHED: 09-15-2010
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Interferon-beta (IFN-?) is one of the main first-line disease-modifying drugs indicated for the treatment of multiple sclerosis (MS). The drug exhibits only limited effectiveness, and does not produce clinical benefits in around 20%-50% of patients. The availability of biomarkers would be beneficial for identification of patients at high risk of treatment failure, before initiation of therapy. Over the last 5 years, the search for such biomarkers has intensified and various promising candidates have been uncovered. Here, we review the main attempts undertaken to identify polymorphic variants associated with response to IFN-? therapy in MS by means of candidate gene approaches and whole-genome association scans. Despite substantial progress made in the field, there is still a long way to go before biomarker discoveries can be incorporated into clinical practice to predict IFN-?-responder status in MS patients.
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IFN-beta pharmacogenomics in multiple sclerosis.
Pharmacogenomics
PUBLISHED: 08-18-2010
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Multiple sclerosis (MS) is a condition of the CNS marked by inflammation and neurodegeneration. Interferon (IFN)-beta was the first, and still is the main, immunomodulatory treatment for MS. Its clinical efficacy is limited, and a proportion of patients, ranging between 20-55%, do not respond to the therapy. Identification and subsequently, implementation in the clinic of biomarkers predictive for individual therapeutic response would facilitate improved patient care in addition to ensuring a more rational provision of this therapy. In this article, we summarize the main findings from studies addressing the pharmacogenomics of clinical response to IFN-beta in MS by either whole-genome association scans, candidate gene or transcriptomics studies. Whole-genome DNA association screens have revealed a high representation of brain-specific genes, and have hinted toward both extracellular ligand-gated ion channels and type I IFNs pathway genes as important categories of genetic IFN-beta response modifiers. One hit, glypican 5 (GPC5), was recently replicated in an independent study of IFN-beta responsiveness. Recent RNA transcriptomics studies have revealed the occurrence of a pre-existing type I IFN gene-expression signature, composed of genes that are predominantly induced by type I IFNs, as a potential contributing feature of poor response to therapy. Thus, while the outlines of a complex polygenic mechanism are gradually being uncovered, the main challenges for the near future will reside in the robust validation of identified response-modifying genes as well as in the decipherment of the mechanistic relationships between these genes and clinical response to IFN-beta.
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High affinity binding of hydrophobic and autoantigenic regions of proinsulin to the 70 kDa chaperone DnaK.
BMC Biochem.
PUBLISHED: 05-10-2010
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Chaperones facilitate proper folding of peptides and bind to misfolded proteins as occurring during periods of cell stress. Complexes of peptides with chaperones induce peptide-directed immunity. Here we analyzed the interaction of (pre)proinsulin with the best characterized chaperone of the hsp70 family, bacterial DnaK.
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Validation of the CD6 and TNFRSF1A loci as risk factors for multiple sclerosis in Spain.
J. Neuroimmunol.
PUBLISHED: 03-02-2010
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A recent meta-analysis of genome-wide association screens coupled to a replication exercise in a combined US/UK collection led to the identification of 4 single nucleotide polymorphisms (SNPs) in three gene loci, i.e. TNFRSF1A, CD6 and IRF8, as novel risk factors for multiple sclerosis with genome-wide level of significance. In the present study, using a combined all-Spain collection of 2515 MS patients and 2942 healthy controls, we demonstrate significant association of rs17824933 in CD6 (P(CMH)=0.004; OR=1.14; 95% CI 1.04-1.24) and of rs1860545 in TNFRSF1A (P(CMH)=0.001; OR=1.15; 95% CI 1.06-1.25) with MS, while the low-frequency coding non-synonymous SNP rs4149584 in TNFRSF1A displayed a trend for association (P(CMH)=0.062; OR=1.27; 95% CI 0.99-1.63). This data reinforce a generic role for CD6 and TNFRSF1A in susceptibility to MS, extending to populations of southern European ancestry.
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Inhibition of secretion of interleukin (IL)-12/IL-23 family cytokines by 4-trifluoromethyl-celecoxib is coupled to degradation via the endoplasmic reticulum stress protein HERP.
J. Biol. Chem.
PUBLISHED: 01-06-2010
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Interleukin-12 (IL-12), p80, and IL-23 are structurally related cytokines sharing a p40 subunit. We have recently demonstrated that celecoxib and its COX-2-independent analogue 4-trifluoromethyl-celecoxib (TFM-C) inhibit secretion but not transcription of IL-12 (p35/p40) and p80 (p40/p40). This is associated with a mechanism involving altered cytokine-chaperone interaction in the endoplasmic reticulum (ER). In the present study, we found that celecoxib and TFM-C also block secretion of IL-23 (p40/p19 heterodimers). Given the putative ER-centric mode of these compounds, we performed a comprehensive RT-PCR analysis of 23 ER-resident chaperones/foldases and associated co-factors. This revealed that TFM-C induced 1.5-3-fold transcriptional up-regulation of calreticulin, GRP78, GRP94, GRP170, ERp72, ERp57, ERdj4, and ERp29. However, more significantly, a 7-fold up-regulation of homocysteine-inducible ER protein (HERP) was observed. HERP is part of a high molecular mass protein complex involved in ER-associated protein degradation (ERAD). Using co-immunoprecipitation assays, we show that TFM-C induces protein interaction of p80 and IL-23 with HERP. Both HERP siRNA knockdown and HERP overexpression coupled to cycloheximide chase assays revealed that HERP is necessary for degradation of intracellularly retained p80 by TFM-C. Thus, our data suggest that targeting cytokine folding in the ER by small molecule drugs could be therapeutically exploited to alleviate inappropriate inflammation in autoimmune conditions.
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Genetic polymorphisms, their allele combinations and IFN-beta treatment response in Irish multiple sclerosis patients.
Pharmacogenomics
PUBLISHED: 07-17-2009
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IFN-beta is widely used as first-line immunomodulatory treatment for multiple sclerosis. Response to treatment is variable (30-50% of patients are nonresponders) and requires a long treatment duration for accurate assessment to be possible. Information about genetic variations that predict responsiveness would allow appropriate treatment selection early after diagnosis, improve patient care, with time saving consequences and more efficient use of resources.
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United Europeans for development of pharmacogenomics in multiple sclerosis network.
Pharmacogenomics
PUBLISHED: 05-20-2009
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Multiple sclerosis (MS) is a chronic inflammatory, disabling disease of the CNS. A recent study has estimated the annual cost of MS in Europe at euro12.5 billion. There is no definitive cure for the disease. Immunomodulatory therapies, such as IFN-beta and glatiramer acetate, are only partially effective. Various new therapies in the final stages of clinical trials are being developed in the absence of efficacy biomarkers. Hence, there is a pressing need for identification of MS treatment response biomarkers. The focus of the multicenter research initiative United Europeans for the development of pharmacogenomics in MS (UEPHA*MS) is to promote and improve training opportunities in the novel supradisciplinary area of pharmacogenomics, biomarker research and systems biology applied to MS. UEPHA*MS is a Marie Curie Initial Training network funded by the 7th Framework Programme of the European Commission. The main scientific goals of this network are both to enhance our knowledge of the mechanisms determining response outcomes of existing immunomodulatory therapies and to identify novel therapeutic opportunities. UEPHA*MS is composed of 11 internationally recognized research teams from five countries with an assortment of expertise in complementary disciplines. The UEPHA*MS network will provide a coherent and internationally competitive platform for the training of young scientists based on multidisciplinary state-of-the-art laboratory-based and network-wide activities. This network will be instrumental in priming young scientists for Europes collective effort toward improved provision of healthcare based on personalized medicine.
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Allelic combinations of immune-response genes as possible composite markers of IFN-? efficacy in multiple sclerosis patients.
Pharmacogenomics
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IFN-? is widely used as the first-line disease-modifying treatment for multiple sclerosis. However, 30-50% of multiple sclerosis patients do not respond to this therapy. Identification of genetic variants and their combinations that predict responsiveness to IFN-? could be useful for treatment prognosis.
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Identification of a functional variant in the KIF5A-CYP27B1-METTL1-FAM119B locus associated with multiple sclerosis.
J. Med. Genet.
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Several studies have highlighted the association of the 12q13.3-12q14.1 region with coeliac disease, type 1 diabetes, rheumatoid arthritis and multiple sclerosis (MS); however, the causal variants underlying diseases are still unclear. The authors sought to identify the functional variant of this region associated with MS.
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Closing the case of APOE in multiple sclerosis: no association with disease risk in over 29 000 subjects.
J. Med. Genet.
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Single nucleotide polymorphisms (SNPs) rs429358 (?4) and rs7412 (?2), both invoking changes in the amino-acid sequence of the apolipoprotein E (APOE) gene, have previously been tested for association with multiple sclerosis (MS) risk. However, none of these studies was sufficiently powered to detect modest effect sizes at acceptable type-I error rates. As both SNPs are only imperfectly captured on commonly used microarray genotyping platforms, their evaluation in the context of genome-wide association studies has been hindered until recently.
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A 4-trifluoromethyl analogue of celecoxib inhibits arthritis by suppressing innate immune cell activation.
Arthritis Res. Ther.
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Celecoxib, a highly specific cyclooxygenase-2 (COX-2) inhibitor has been reported to have COX-2-independent immunomodulatory effects. However, celecoxib itself has only mild suppressive effects on arthritis. Recently, we reported that a 4-trifluoromethyl analogue of celecoxib (TFM-C) with 205-fold lower COX-2-inhibitory activity inhibits secretion of IL-12 family cytokines through a COX-2-independent mechanism that involves Ca2+-mediated intracellular retention of the IL-12 polypeptide chains. In this study, we explored the capacity of TFM-C as a new therapeutic agent for arthritis.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.