03039nas a2200385   4500008004100000022001400041245012200055210006900177260001600246300000700262490000700269520175100276653001502027653001102042653001302053653004202066653001102108653002302119653001802142100002802160700002302188700002602211700002402237700002602261700003202287700003302319700002802352700003002380700001802410700002102428700002002449700001902469700002502488856014002513       2025                        eng d  a1479-587600aA genomic strategy for precision medicine in rare diseases: integrating customized algorithms into clinical practice.0 agenomic strategy for precision medicine in rare diseases integra  c2025 Jan 20  a860 v233 a<p><b>BACKGROUND: </b>Despite the use of Next-Generation Sequencing (NGS) as the gold standard for the diagnosis of rare diseases, its clinical implementation has been challenging, limiting the cost-effectiveness of NGS and the understanding, control and safety essential for decision-making in clinical applications. Here, we describe a personalized NGS-based strategy integrating precision medicine into a public healthcare system and its implementation in the routine diagnosis process during a five-year pilot program.</p><p><b>METHODS: </b>Our approach involved customized probe designs, the generation of virtual panels and the development of a personalized medicine module (PMM) for variant prioritization. This strategy was applied to 6500 individuals including 6267 index patients and 233 NGS-based carrier screenings.</p><p><b>RESULTS: </b>Causative variants were identified in 2061 index patients (average 32.9%, ranging from 12 to 62% by condition). Also, 131 autosomal-recessive cases could be partially genetically diagnosed. These results led to over 5000 additional studies including carrier, prenatal and preimplantational tests or pharmacological and gene therapy treatments.</p><p><b>CONCLUSION: </b>This strategy has shown promising improvements in the diagnostic rate, facilitating timely diagnosis and gradually expanding our services portfolio for rare diseases. The steps taken towards the integration of clinical and genomic data are opening new possibilities for conducting both retrospective and prospective healthcare studies. Overall, this study represents a major milestone in the ongoing efforts to improve our understanding and clinical management of rare diseases, a crucial area of medical research and care.</p>10aAlgorithms10aFemale10aGenomics10aHigh-Throughput Nucleotide Sequencing10aHumans10aPrecision Medicine10arare diseases1 aMéndez-Vidal, Cristina1 aBravo-Gil, Nereida1 aPerez-Florido, Javier1 aMarcos-Luque, Irene1 aFernández, Raquel, M1 aFernandez-Rueda, Jose, Luis1 adel Pozo, María, González-1 aMartín-Sánchez, Marta1 aFernández-Suárez, Elena1 aMena, Marcela1 aCarmona, Rosario1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo  uhttp://clinbioinfosspa.es/content/genomic-strategy-precision-medicine-rare-diseases-integrating-customized-algorithms-clinical-practice03981nas a2200661   4500008004100000022001400041245015900055210006900214260001600283300000900299490000700308520173000315653001002045653000902055653001602064653001302080653002502093653001002118653001102128653003202139653003002171653002102201653000902222653001102231653001802242653000902260653001602269653001702285653001802302100004002320700002902360700003102389700003302420700002002453700002602473700002902499700003502528700003002563700003402593700003002627700002502657700003602682700003002718700003402748700002802782700002802810700002902838700003002867700002902897700003602926700003102962700003502993700003203028700003303060700001903093700002603112856018103138       2025                        eng d  a2045-232200aMetatranscriptomic analysis reveals gut microbiome bacterial genes in pyruvate and amino acid metabolism associated with hyperuricemia and gout in humans.0 aMetatranscriptomic analysis reveals gut microbiome bacterial gen  c2025 Mar 22  a99810 v153 a<p>Several pathologies with metabolic origin, such as hyperuricemia and gout, have been associated with the gut microbiota taxonomic profile. However, there is no evidence of which bacterial genes are being expressed in the gut microbiome, and of their potential effects on hyperuricemia and gout. We sequenced the RNA of 26 fecal samples from 10 healthy normouricemic controls, 10 with asymptomatic hyperuricemia (AH), and six gout patients. The coding sequences were mapped to KEGG orthologues (KO). We compared the expression levels using generalized linear models and validated the expression of four KO in a larger sample by qRT-PCR. A distinct genetic expression pattern was identified among groups. AH individuals and gout patients showed an over-expression of KOs mainly related to pyruvate metabolism (Log2foldchange > 23, p-adj ≤ 3.56 × 10), the pentose pathway (Log2foldchange > 24, p-adj < 1.10 × 10) and purine metabolism (Log2foldchange > 22, p-adj < 1.25 × 10). AH subjects had lower expression of KO related to glycine metabolism (Log2foldchange=-18, p-adj < 1.72 × 10) than controls. Gout patients had lower expression (Log2foldchange=-22.42, p-adj < 3.31 × 10) of a KO involved in phenylalanine biosynthesis, in comparison to controls and AH subjects. The over-expression seen for the KO related to pyruvate metabolism and the pentose pathway in gout patients´ microbiome was validated. There is a differential gene expression pattern in the gut microbiome of normouricemic individuals, AH subjects and gout patients. These differences are mainly located in metabolic pathways involved in acetate precursors and bioavailability of amino acids.</p>10aAdult10aAged10aAmino Acids10aBacteria10aCase-Control Studies10aFeces10aFemale10aGastrointestinal Microbiome10aGene Expression Profiling10aGenes, Bacterial10aGout10aHumans10aHyperuricemia10aMale10aMiddle Aged10aPyruvic Acid10aTranscriptome1 aMartínez-Nava, Gabriela, Angélica1 aAltamirano-Molina, Efren1 aVázquez-Mellado, Janitzia1 aCasimiro-Soriguer, Carlos, S1 aDopazo, Joaquin1 aLozada-Pérez, Carlos1 aHerrera-López, Brígida1 aMartínez-Gómez, Laura, Edith1 aMartínez-Armenta, Carlos1 aGuido-Gómora, Dafne, Lissete1 aValle-Gutiérrez, Sarahí1 aSuarez-Ahedo, Carlos1 aCamacho-Rea, María, Del Carmen1 aMartínez-García, Mireya1 aGutiérrez-Esparza, Guadalupe1 aAmezcua-Guerra, Luis, M1 aZamudio-Cuevas, Yessica1 aMartínez-Flores, Karina1 aFernández-Torres, Javier1 aBurguete-García, Ana, I1 aOrbe-Orihuela, Yaneth, Citlalli1 aLagunas-Martínez, Alfredo1 aMéndez-Salazar, Eder, Orlando1 aFrancisco-Balderas, Adriana1 aPalacios-González, Berenice1 aPineda, Carlos1 aLópez-Reyes, Alberto  uhttp://clinbioinfosspa.es/content/metatranscriptomic-analysis-reveals-gut-microbiome-bacterial-genes-pyruvate-and-amino-acid-metabolism-associated-hyperuricemia-and-gout-humans02868nas a2200385   4500008004100000022001400041245005800055210005600113260001600169300001000185490000700195520182400202653001002026653000902036653002202045653002502067653001702092653001302109653002802122653001102150653001102161653000902172653001602181653002602197653001502223100002402238700002002262700002102282700001502303700001802318700002202336700001402358700002202372856008802394       2024                        eng d  a2045-232200aAripiprazole as protector against COVID-19 mortality.0 aAripiprazole as protector against COVID19 mortality  c2024 May 29  a123620 v143 a<p>The relation of antipsychotics with severe Coronavirus Disease 19 (COVID-19) outcomes is a matter of debate since the beginning of the pandemic. To date, controversial results have been published on this issue. We aimed to prove whether antipsychotics might exert adverse or protective effects against fatal outcomes derived from COVID-19. A population-based retrospective cohort study (January 2020 to November 2020) comprising inpatients (15,968 patients) who were at least 18 years old and had a laboratory-confirmed COVID-19 infection. Two sub-cohorts were delineated, comprising a total of 2536 inpatients: individuals who either had no prescription medication or were prescribed an antipsychotic within the 15 days preceding hospitalization. We conducted survival and odds ratio analyses to assess the association between antipsychotic use and mortality, reporting both unadjusted and covariate-adjusted results. We computed the average treatment effects, using the untreated group as the reference, and the average treatment effect on the treated, focusing solely on the antipsychotic-treated population. Among the eight antipsychotics found to be in use, only aripiprazole showed a significant decrease in the risk of death from COVID-19 [adjusted odds ratio (OR) = 0.86; 95% CI, 0.79-0.93, multiple-testing adjusted p-value < 0.05]. Importantly, these findings were consistent for both covariate-adjusted and unadjusted analyses. Aripiprazole has been shown to have a differentiated beneficial effect in protecting against fatal clinical outcome in COVID-19 infected individuals. We speculate that the differential effect of aripiprazole on controlling immunological pathways and inducible inflammatory enzymes, that are critical in COVID19 illness, may be associated with our findings herein.</p>10aAdult10aAged10aAged, 80 and over10aAntipsychotic Agents10aAripiprazole10aCOVID-1910aCOVID-19 Drug Treatment10aFemale10aHumans10aMale10aMiddle Aged10aRetrospective Studies10aSARS-CoV-21 aLoucera-Muñecas, C1 aCanal-Rivero, M1 aRuiz-Veguilla, M1 aCarmona, R1 aBostelmann, G1 aGarrido-Torres, N1 aDopazo, J1 aCrespo-Facorro, B  uhttp://clinbioinfosspa.es/content/aripiprazole-protector-against-covid-19-mortality02821nas a2200517   4500008004100000022001400041245009100055210006900146260001600215490000700231520126600238653001901504653001001523653001101533653001901544653002201563653002501585653001801610653001101628653000901639653003601648653001001684653002801694100002001722700002201742700002801764700002901792700002001821700002001841700002801861700002301889700002001912700002101932700002101953700002601974700002102000700002602021700002402047700001902071700002002090700001702110700002502127700001902152700002502171856010702196       2024                        eng d  a2073-442500aCharacterization of the Common Genetic Variation in the Spanish Population of Navarre.0 aCharacterization of the Common Genetic Variation in the Spanish   c2024 May 040 v153 a<p>Large-scale genomic studies have significantly increased our knowledge of genetic variability across populations. Regional genetic profiling is essential for distinguishing common benign variants from disease-causing ones. To this end, we conducted a comprehensive characterization of exonic variants in the population of Navarre (Spain), utilizing whole genome sequencing data from 358 unrelated individuals of Spanish origin. Our analysis revealed 61,410 biallelic single nucleotide variants (SNV) within the Navarrese cohort, with 35% classified as common (MAF > 1%). By comparing allele frequency data from 1000 Genome Project (excluding the Iberian cohort of Spain, IBS), Genome Aggregation Database, and a Spanish cohort (including IBS individuals and data from Medical Genome Project), we identified 1069 SNVs common in Navarre but rare (MAF ≤ 1%) in all other populations. We further corroborated this observation with a second regional cohort of 239 unrelated exomes, which confirmed 676 of the 1069 SNVs as common in Navarre. In conclusion, this study highlights the importance of population-specific characterization of genetic variation to improve allele frequency filtering in sequencing data analysis to identify disease-causing variants.</p>10aCohort Studies10aExome10aFemale10aGene Frequency10aGenetic Variation10aGenetics, Population10aGenome, Human10aHumans10aMale10aPolymorphism, Single Nucleotide10aSpain10aWhole Genome Sequencing1 aMaillo, Alberto1 aHuergo, Estefania1 aApellániz-Ruiz, María1 aUrrutia-Lafuente, Edurne1 aMiranda, María1 aSalgado, Josefa1 aPasalodos-Sanchez, Sara1 aDelgado-Mora, Luna1 aTeijido, Óscar1 aGoicoechea, Ibai1 aCarmona, Rosario1 aPerez-Florido, Javier1 aAquino, Virginia1 aLópez-López, Daniel1 aPeña-Chilet, Maria1 aBeltran, Sergi1 aDopazo, Joaquin1 aLasa, Iñigo1 aBeloqui, Juan, José1 aAlonso, Ángel1 aGomez-Cabrero, David  uhttp://clinbioinfosspa.es/content/characterization-common-genetic-variation-spanish-population-navarre04620nas a2201141   4500008004100000022001400041245011000055210006900165260000900234300001200243490000700255520126600262653002401528653001301552653002301565653001101588653001501599653002001614100001901634700002301653700002201676700002101698700002001719700002301739700002101762700002601783700001901809700002001828700001901848700002201867700002301889700002401912700001701936700002101953700001701974700001601991700002402007700002502031700002502056700002302081700002302104700002702127700002402154700001602178700002102194700002602215700002502241700002102266700002102287700001902308700003202327700002102359700002202380700002002402700001902422700002602441700001802467700001802485700002302503700002102526700001902547700001902566700002202585700001802607700001902625700001802644700002302662700001802685700002002703700001902723700003302742700002602775700002702801700002502828700002302853700001802876700002302894700001702917700002402934700001802958700002202976700002502998700002003023700002303043700002003066700002603086700002003112700001903132700002203151700002203173700002003195700002303215700002103238700001803259700002403277710003503301856014203336       2024                        eng d  a1664-322400aDrug-target identification in COVID-19 disease mechanisms using computational systems biology approaches.0 aDrugtarget identification in COVID19 disease mechanisms using co  c2023  a12828590 v143 a<p><b>INTRODUCTION: </b>The COVID-19 Disease Map project is a large-scale community effort uniting 277 scientists from 130 Institutions around the globe. We use high-quality, mechanistic content describing SARS-CoV-2-host interactions and develop interoperable bioinformatic pipelines for novel target identification and drug repurposing.</p><p><b>METHODS: </b>Extensive community work allowed an impressive step forward in building interfaces between Systems Biology tools and platforms. Our framework can link biomolecules from omics data analysis and computational modelling to dysregulated pathways in a cell-, tissue- or patient-specific manner. Drug repurposing using text mining and AI-assisted analysis identified potential drugs, chemicals and microRNAs that could target the identified key factors.</p><p><b>RESULTS: </b>Results revealed drugs already tested for anti-COVID-19 efficacy, providing a mechanistic context for their mode of action, and drugs already in clinical trials for treating other diseases, never tested against COVID-19.</p><p><b>DISCUSSION: </b>The key advance is that the proposed framework is versatile and expandable, offering a significant upgrade in the arsenal for virus-host interactions and other complex pathologies.</p>10aComputer Simulation10aCOVID-1910adrug repositioning10aHumans10aSARS-CoV-210aSystems biology1 aNiarakis, Anna1 aOstaszewski, Marek1 aMazein, Alexander1 aKuperstein, Inna1 aKutmon, Martina1 aGillespie, Marc, E1 aFunahashi, Akira1 aAcencio, Marcio, Luis1 aHemedan, Ahmed1 aAichem, Michael1 aKlein, Karsten1 aCzauderna, Tobias1 aBurtscher, Felicia1 aYamada, Takahiro, G1 aHiki, Yusuke1 aHiroi, Noriko, F1 aHu, Finterly1 aPham, Nhung1 aEhrhart, Friederike1 aWillighagen, Egon, L1 aValdeolivas, Alberto1 aDugourd, Aurélien1 aMessina, Francesco1 aEsteban-Medina, Marina1 aPeña-Chilet, Maria1 aRian, Kinza1 aSoliman, Sylvain1 aAghamiri, Sara, Sadat1 aPuniya, Bhanwar, Lal1 aNaldi, Aurélien1 aHelikar, Tomáš1 aSingh, Vidisha1 aFernández, Marco, Fariñas1 aBermudez, Viviam1 aTsirvouli, Eirini1 aMontagud, Arnau1 aNoël, Vincent1 aPonce-de-Leon, Miguel1 aMaier, Dieter1 aBauch, Angela1 aGyori, Benjamin, M1 aBachman, John, A1 aLuna, Augustin1 aPiñero, Janet1 aFurlong, Laura, I1 aBalaur, Irina1 aRougny, Adrien1 aJarosz, Yohan1 aOverall, Rupert, W1 aPhair, Robert1 aPerfetto, Livia1 aMatthews, Lisa1 aRex, Devasahayam, Arokia Bal1 aOrlic-Milacic, Marija1 aGomez, Luis, Cristobal1 aDe Meulder, Bertrand1 aRavel, Jean, Marie1 aJassal, Bijay1 aSatagopam, Venkata1 aWu, Guanming1 aGolebiewski, Martin1 aGawron, Piotr1 aCalzone, Laurence1 aBeckmann, Jacques, S1 aEvelo, Chris, T1 aD'Eustachio, Peter1 aSchreiber, Falk1 aSaez-Rodriguez, Julio1 aDopazo, Joaquin1 aKuiper, Martin1 aValencia, Alfonso1 aWolkenhauer, Olaf1 aKitano, Hiroaki1 aBarillot, Emmanuel1 aAuffray, Charles1 aBalling, Rudi1 aSchneider, Reinhard1 aCOVID-19 Disease Map Community  uhttp://clinbioinfosspa.es/content/drug-target-identification-covid-19-disease-mechanisms-using-computational-systems-biology-approaches-004049nas a2200517   4500008004100000022001400041245010200055210006900157260001600226300001300242490000700255520251300262653001502775653001002790653000902800653002202809653002602831653002902857653002502886653001002911653002102921653001802942653003102960653001702991653001103008653001303019653001103032653001103043653000903054653003203063653001603095653001403111653001003125653001703135653001603152100003103168700002903199700003303228700003003261700002103291700001703312700002003329700002003349700003403369856012803403       2024                        eng d  a2165-049700aGenotypic characterization and antimicrobial susceptibility of human  isolates in Southern Spain.0 aGenotypic characterization and antimicrobial susceptibility of h  c2024 Oct 03  ae01028240 v123 a<p> is the main cause of bacterial gastroenteritis and a public health problem worldwide. Little information is available on the genotypic characteristics of human  in Spain. This study is based on an analysis of the resistome, virulome, and phylogenetic relationship, antibiogram prediction, and antimicrobial susceptibility of 114 human isolates of  from a tertiary hospital in southern Spain from October 2020 to June 2023. The isolates were sequenced using Illumina technology, and a bioinformatic analysis was subsequently performed. The susceptibility of  isolates to ciprofloxacin, tetracycline, and erythromycin was also tested. The resistance rates for each antibiotic were 90.3% for ciprofloxacin, 66.7% for tetracycline, and 0.88% for erythromycin. The fluoroquinolone resistance rate obtained is well above the European average (69.1%). CC-21 ( = 23), ST-572 ( = 13), and ST-6532 ( = 13) were the most prevalent clonal complexes (CCs) and sequence types (STs). In the virulome, the , and  genes were detected in all the isolates. A prevalence of 20.1% was obtained for the genes  and , which are related to the pathogenesis of Guillain-Barré syndrome (GBS). The prevalence of the main antimicrobial resistance markers detected were CmeABC (92.1%), RE-cmeABC (7.9%), the T86I substitution in  (88.9%),  (72.6%) (65.8%), and  (17.1%). High antibiogram prediction rates (>97%) were obtained, except for in the case of the erythromycin-resistant phenotype. This study contributes significantly to the knowledge of  genomics for the prevention, treatment, and control of infections caused by this pathogen.IMPORTANCEDespite being the pathogen with the greatest number of gastroenteritis cases worldwide,  remains a poorly studied microorganism. A sustained increase in fluoroquinolone resistance in human isolates is a problem when treating  infections. The development of whole genome sequencing (WGS) techniques has allowed us to better understand the genotypic characteristics of this pathogen and relate them to antibiotic resistance phenotypes. These techniques complement the data obtained from the phenotypic analysis of  isolates. The zoonotic transmission of  through the consumption of contaminated poultry supports approaching the study of this pathogen through "One Health" approach. In addition, due to the limited information on the genomic characteristics of  in Spain, this study provides important data and allows us to compare the results with those obtained in other countries.</p>10aAdolescent10aAdult10aAged10aAged, 80 and over10aAnti-Bacterial Agents10aCampylobacter Infections10aCampylobacter jejuni10aChild10aChild, Preschool10aCiprofloxacin10aDrug Resistance, Bacterial10aErythromycin10aFemale10aGenotype10aHumans10aInfant10aMale10aMicrobial Sensitivity Tests10aMiddle Aged10aPhylogeny10aSpain10aTetracycline10aYoung Adult1 aFernández-Palacios, Pablo1 aGalán-Sánchez, Fátima1 aCasimiro-Soriguer, Carlos, S1 aJurado-Tarifa, Estefanía1 aArroyo, Federico1 aLara, María1 aChaves, Alberto1 aDopazo, Joaquin1 aRodriguez-Iglesias, Manuel, A  uhttp://clinbioinfosspa.es/content/genotypic-characterization-and-antimicrobial-susceptibility-human-isolates-southern-spain04177nas a2200709   4500008004100000022001400041245013800055210006900193260001600262300000800278490000700286520187400293653001202167653003802179653002102217653003002238653001102268653004302279653001902322653001102341653001902352653000902371653001402380653001202394653002402406653003302430653001602463653003702479100002002516700003102536700002702567700002402594700002802618700002502646700002702671700002302698700002702721700002802748700001802776700002002794700002802814700002502842700002502867700002402892700002902916700003502945700002102980700003103001700002103032700001903053700002803072700001803100700002203118700002903140700003103169700002303200700002003223700001703243700002803260700002503288856015403313       2024                        eng d  a1420-907100aHMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS): A Spanish Group for Research on Sarcomas (GEIS) study.0 aHMGA1 regulates trabectedin sensitivity in advanced softtissue s  c2024 May 17  a2190 v813 a<p>HMGA1 is a structural epigenetic chromatin factor that has been associated with tumor progression and drug resistance. Here, we reported the prognostic/predictive value of HMGA1 for trabectedin in advanced soft-tissue sarcoma (STS) and the effect of inhibiting HMGA1 or the mTOR downstream pathway in trabectedin activity. The prognostic/predictive value of HMGA1 expression was assessed in a cohort of 301 STS patients at mRNA (n = 133) and protein level (n = 272), by HTG EdgeSeq transcriptomics and immunohistochemistry, respectively. The effect of HMGA1 silencing on trabectedin activity and gene expression profiling was measured in leiomyosarcoma cells. The effect of combining mTOR inhibitors with trabectedin was assessed on cell viability in vitro studies, whereas in vivo studies tested the activity of this combination. HMGA1 mRNA and protein expression were significantly associated with worse progression-free survival of trabectedin and worse overall survival in STS. HMGA1 silencing sensitized leiomyosarcoma cells for trabectedin treatment, reducing the spheroid area and increasing cell death. The downregulation of HGMA1 significantly decreased the enrichment of some specific gene sets, including the PI3K/AKT/mTOR pathway. The inhibition of mTOR, sensitized leiomyosarcoma cultures for trabectedin treatment, increasing cell death. In in vivo studies, the combination of rapamycin with trabectedin downregulated HMGA1 expression and stabilized tumor growth of 3-methylcholantrene-induced sarcoma-like models. HMGA1 is an adverse prognostic factor for trabectedin treatment in advanced STS. HMGA1 silencing increases trabectedin efficacy, in part by modulating the mTOR signaling pathway. Trabectedin plus mTOR inhibitors are active in preclinical models of sarcoma, downregulating HMGA1 expression levels and stabilizing tumor growth.</p>10aAnimals10aAntineoplastic Agents, Alkylating10aCell Line, Tumor10aDrug Resistance, Neoplasm10aFemale10aGene Expression Regulation, Neoplastic10aHMGA1a Protein10aHumans10aLeiomyosarcoma10aMice10aPrognosis10aSarcoma10aSignal Transduction10aTOR Serine-Threonine Kinases10aTrabectedin10aXenograft Model Antitumor Assays1 aMoura, David, S1 aMondaza-Hernandez, Jose, L1 aSanchez-Bustos, Paloma1 aPeña-Chilet, Maria1 aCordero-Varela, Juan, A1 aLopez-Alvarez, Maria1 aCarrillo-Garcia, Jaime1 aMartin-Ruiz, Marta1 aRomero-Gonzalez, Pablo1 aRenshaw-Calderon, Marta1 aRamos, Rafael1 aMarcilla, David1 aAlvarez-Alegret, Ramiro1 aAgra-Pujol, Carolina1 aIzquierdo, Francisco1 aOrtega-Medina, Luis1 aMartin-Davila, Francisco1 aHernandez-Leon, Carmen, Nieves1 aRomagosa, Cleofe1 aSalgado, Maria, Angeles Va1 aLavernia, Javier1 aBagué, Silvia1 aMayodormo-Aranda, Empar1 aAlvarez, Rosa1 aValverde, Claudia1 aMartinez-Trufero, Javier1 aCastilla-Ramirez, Carolina1 aGutierrez, Antonio1 aDopazo, Joaquin1 aHindi, Nadia1 aGarcia-Foncillas, Jesus1 aMartin-Broto, Javier  uhttp://clinbioinfosspa.es/content/hmga1-regulates-trabectedin-sensitivity-advanced-soft-tissue-sarcoma-sts-spanish-group-research-sarcomas-geis-study03334nas a2200445   4500008004100000022001400041245013500055210006900190260001600259300001000275490000700285520187800292653001202170653003102182653002202213653001302235653001102248653001502259653002202274653002802296100003302324700002602357700002302383700001702406700001902423700003302442700001802475700002202493700002702515700002202542700002602564700002002590700001902610700002002629700002802649700002302677700002002700700002002720856014802740       2024                        eng d  a2045-232200aThe integrated genomic surveillance system of Andalusia (SIEGA) provides a One Health regional resource connected with the clinic.0 aintegrated genomic surveillance system of Andalusia SIEGA provid  c2024 Aug 19  a192000 v143 a<p>The One Health approach, recognizing the interconnectedness of human, animal, and environmental health, has gained significance amid emerging zoonotic diseases and antibiotic resistance concerns. This paper aims to demonstrate the utility of a collaborative tool, the SIEGA, for monitoring infectious diseases across domains, fostering a comprehensive understanding of disease dynamics and risk factors, highlighting the pivotal role of One Health surveillance systems. Raw whole-genome sequencing is processed through different species-specific open software that additionally reports the presence of genes associated to anti-microbial resistances and virulence. The SIEGA application is a Laboratory Information Management System, that allows customizing reports, detect transmission chains, and promptly alert on alarming genetic similarities. The SIEGA initiative has successfully accumulated a comprehensive collection of more than 1900 bacterial genomes, including Salmonella enterica, Listeria monocytogenes, Campylobacter jejuni, Escherichia coli, Yersinia enterocolitica and Legionella pneumophila, showcasing its potential in monitoring pathogen transmission, resistance patterns, and virulence factors. SIEGA enables customizable reports and prompt detection of transmission chains, highlighting its contribution to enhancing vigilance and response capabilities. Here we show the potential of genomics in One Health surveillance when supported by an appropriate bioinformatic tool. By facilitating precise disease control strategies and antimicrobial resistance management, SIEGA enhances global health security and reduces the burden of infectious diseases. The integration of health data from humans, animals, and the environment, coupled with advanced genomics, underscores the importance of a holistic One Health approach in mitigating health threats.</p>10aAnimals10aDrug Resistance, Bacterial10aGenome, Bacterial10aGenomics10aHumans10aOne Health10aVirulence Factors10aWhole Genome Sequencing1 aCasimiro-Soriguer, Carlos, S1 aPerez-Florido, Javier1 aRobles, Enrique, A1 aLara, María1 aAguado, Andrea1 aIglesias, Manuel, A Rodrígu1 aLepe, Jose, A1 aGarcía, Federico1 aPérez-Alegre, Mónica1 aAndújar, Eloísa1 aJiménez, Victoria, E1 aCamino, Lola, P1 aLoruso, Nicola1 aAmeyugo, Ulises1 aVazquez, Isabel, María1 aLozano, Carlota, M1 aChaves, Alberto1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/integrated-genomic-surveillance-system-andalusia-siega-provides-one-health-regional-resource-connected-clinic02531nas a2200373   4500008004100000022001400041245010000055210006900155260001600224490000700240520133200247653003101579653001701610653002001627653001101647653000901658653001301667653002501680100002301705700002801728700003101756700002501787700002101812700001601833700002101849700002501870700002101895700001901916700001601935700002701951700002901978700001902007856013102026       2024                        eng d  a2073-440900aPrimary Ciliary Dyskinesia and Retinitis Pigmentosa: Novel  Variant and Possible Modifier Gene.0 aPrimary Ciliary Dyskinesia and Retinitis Pigmentosa Novel Varian  c2024 Mar 160 v133 a<p>We report a novel  missense variant co-segregated with a familial X-linked retinitis pigmentosa (XLRP) case. The brothers were hemizygous for this variant, but only the proband presented with primary ciliary dyskinesia (PCD). Thus, we aimed to elucidate the role of the  variant and other modifier genes in the phenotypic variability observed in the family and its impact on motile cilia. The pathogenicity of the variant on the RPGR protein was evaluated by in vitro studies transiently transfecting the mutated  gene, and immunofluorescence analysis on nasal brushing samples. Whole-exome sequencing was conducted to identify potential modifier variants. In vitro studies showed that the mutated RPGR protein could not localise to the cilium and impaired cilium formation. Accordingly, RPGR was abnormally distributed in the siblings' nasal brushing samples. In addition, a missense variant in  was identified. The concurrent  variant influenced ciliary mislocalisation of the protein. We provide a comprehensive characterisation of motile cilia in this XLRP family, with only the proband presenting PCD symptoms. The variant's pathogenicity was confirmed, although it alone does not explain the respiratory symptoms. Finally, the  gene may be a potential modifier for respiratory symptoms in patients with  mutations.</p>10aCiliary Motility Disorders10aEye Proteins10aGenes, Modifier10aHumans10aMale10amutation10aRetinitis pigmentosa1 aBaz-Redón, Noelia1 aSánchez-Bellver, Laura1 aFernández-Cancio, Mónica1 aRovira-Amigo, Sandra1 aBurgoyne, Thomas1 aRanjit, Rai1 aAquino, Virginia1 aToro-Barrios, Noemí1 aCarmona, Rosario1 aPolverino, Eva1 aCols, Maria1 aMoreno-Galdó, Antonio1 aCamats-Tarruella, Núria1 aMarfany, Gemma  uhttp://clinbioinfosspa.es/content/primary-ciliary-dyskinesia-and-retinitis-pigmentosa-novel-variant-and-possible-modifier-gene02883nas a2200457   4500008004100000022001400041245011500055210006900170260001600239300001200255490000700267520134200274653003101616653001101647653003101658653003601689653003801725653002301763653001101786653000901797653001601806653003601822653003401858653005101892653002801943100002001971700002701991700002202018700002302040700002502063700001802088700001702106700002002123700002502143700003102168700001802199700001702217700002802234700002502262856013802287       2024                        eng d  a1468-624400aShared germline genomic variants in two patients with double primary gastrointestinal stromal tumours (GISTs).0 aShared germline genomic variants in two patients with double pri  c2024 Sep 24  a927-9340 v613 a<p><b>BACKGROUND: </b>Gastrointestinal stromal tumours (GISTs) are prevalent mesenchymal tumours of the gastrointestinal tract, commonly exhibiting structural variations in  and  genes. While the mutational profiling of somatic tumours is well described, the genes behind the susceptibility to develop GIST are not yet fully discovered. This study explores the genomic landscape of two primary GIST cases, aiming to identify shared germline pathogenic variants and shed light on potential key players in tumourigenesis.</p><p><b>METHODS: </b>Two patients with distinct genotypically and phenotypically GISTs underwent germline whole genome sequencing. CNV and single nucleotide variant (SNV) analyses were performed.</p><p><b>RESULTS: </b>Both patients harbouring low-risk GISTs with different mutations ( and ) shared homozygous germline pathogenic deletions in both  and  genes. CNV analysis revealed additional shared pathogenic deletions in other genes such as . No particular pathogenic SNV shared by both patients was detected.</p><p><b>CONCLUSION: </b>Our study provides new insights into germline variants that can be associated with the development of GISTs, namely,  and  deep deletions. Further functional validation is warranted to elucidate the precise contributions of identified germline mutations in GIST development.</p>10aDNA Copy Number Variations10aFemale10aGastrointestinal Neoplasms10aGastrointestinal Stromal Tumors10aGenetic Predisposition to Disease10aGerm-Line Mutation10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aProto-Oncogene Proteins c-kit10aReceptor, Platelet-Derived Growth Factor alpha10aWhole Genome Sequencing1 aMoura, David, S1 aLópez, Daniel, López1 adi Lernia, Davide1 aMartin-Ruiz, Marta1 aLopez-Alvarez, Maria1 aRamos, Rafael1 aMerino, Jose1 aDopazo, Joaquin1 aLopez-Guerrero, Jose1 aMondaza-Hernandez, Jose, L1 aRomero, Pablo1 aHindi, Nadia1 aGarcia-Foncillas, Jesus1 aMartin-Broto, Javier  uhttp://clinbioinfosspa.es/content/shared-germline-genomic-variants-two-patients-double-primary-gastrointestinal-stromal-tumours-gists02288nas a2200301   4500008004100000022001400041245015200055210006900207260001600276300000900292490000800301520121000309653001201519653001301531653002101544653001101565653004001576653001501616653003201631100002601663700002301689700001701712700002001729700002601749700002001775700002201795856016901817       2023                        eng d  a1469-440900aEvaluation of a combined detection of SARS-CoV-2 and its variants using real-time allele-specific PCR strategy: an advantage for clinical practice.0 aEvaluation of a combined detection of SARSCoV2 and its variants   c2023 Nov 24  ae2010 v1513 a<p>This study aimed to assess the ability of a real-time reverse transcription polymerase chain reaction (RT-PCR) with multiple targets to detect SARS-CoV-2 and its variants in a single test. Nasopharyngeal specimens were collected from patients in Granada, Spain, between January 2021 and December 2022. Five allele-specific RT-PCR kits were used sequentially, with each kit designed to detect a predominant variant at the time. When the Alpha variant was dominant, the kit included the HV69/70 deletion, E and N genes. When Delta replaced Alpha, the kit incorporated the L452R mutation in addition to E and N genes. When Omicron became dominant, L452R was replaced with the N679K mutation. Before incorporating each variant kit, a comparative analysis was carried out with SARS-CoV-2 whole genome sequencing (WGS). The results demonstrated that RT-PCR with multiple targets can provide rapid and effective detection of SARS-CoV-2 and its variants in a single test. A very high degree of agreement (96.2%) was obtained between the comparison of RT-PCR and WGS. Allele-specific RT-PCR assays make it easier to implement epidemiological surveillance systems for effective public health decision making.</p>10aAlleles10aCOVID-1910aCOVID-19 Testing10aHumans10aReal-Time Polymerase Chain Reaction10aSARS-CoV-210aSensitivity and Specificity1 aChaves-Blanco, Lucía1 ade Salazar, Adolfo1 aFuentes, Ana1 aViñuela, Laura1 aPerez-Florido, Javier1 aDopazo, Joaquin1 aGarcía, Federico  uhttp://clinbioinfosspa.es/content/evaluation-combined-detection-sars-cov-2-and-its-variants-using-real-time-allele-specific-pcr-strategy-advantage-clinical-practice00578nas a2200169   4500008004100000022001400041245007500055210006900130260001300199300001100212490000800223653001300231653001900244653001100263110003800274856009600312       2023                        eng d  a1476-468700aA second update on mapping the human genetic architecture of COVID-19.0 asecond update on mapping the human genetic architecture of COVID  c2023 Sep  aE7-E260 v62110aCOVID-1910aHuman Genetics10aHumans1 aCOVID-19 Host Genetics Initiative  uhttp://clinbioinfosspa.es/content/second-update-mapping-human-genetic-architecture-covid-1902570nas a2200457   4500008004100000022001400041245008300055210006900138260001600207490000700223520116500230653001301395653001801408653001101426653001301437653001401450653001401464653001501478100002001493700002601513700003301539700002501572700002101597700002301618700003201641700003101673700002101704700002901725700002601754700002001780700002501800700002701825700002801852700002301880700002301903700002001926700001801946700002201964700002001986856010602006       2022                        eng d  a1999-491500aAssessing the Impact of SARS-CoV-2 Lineages and Mutations on Patient Survival.0 aAssessing the Impact of SARSCoV2 Lineages and Mutations on Patie  c2022 Aug 270 v143 a<p><b>OBJECTIVES: </b>More than two years into the COVID-19 pandemic, SARS-CoV-2 still remains a global public health problem. Successive waves of infection have produced new SARS-CoV-2 variants with new mutations for which the impact on COVID-19 severity and patient survival is uncertain.</p><p><b>METHODS: </b>A total of 764 SARS-CoV-2 genomes, sequenced from COVID-19 patients, hospitalized from 19th February 2020 to 30 April 2021, along with their clinical data, were used for survival analysis.</p><p><b>RESULTS: </b>A significant association of B.1.1.7, the alpha lineage, with patient mortality (log hazard ratio (LHR) = 0.51, C.I. = [0.14,0.88]) was found upon adjustment by all the covariates known to affect COVID-19 prognosis. Moreover, survival analysis of mutations in the SARS-CoV-2 genome revealed 27 of them were significantly associated with higher mortality of patients. Most of these mutations were located in the genes coding for the S, ORF8, and N proteins.</p><p><b>CONCLUSIONS: </b>This study illustrates how a combination of genomic and clinical data can provide solid evidence for the impact of viral lineage on patient survival.</p>10aCOVID-1910aGenome, Viral10aHumans10amutation10aPandemics10aPhylogeny10aSARS-CoV-21 aLoucera, Carlos1 aPerez-Florido, Javier1 aCasimiro-Soriguer, Carlos, S1 aOrtuno, Francisco, M1 aCarmona, Rosario1 aBostelmann, Gerrit1 aMartínez-González, Javier1 aMuñoyerro-Muñiz, Dolores1 aVillegas, Román1 aRodríguez-Baño, Jesús1 aRomero-Gómez, Manuel1 aLorusso, Nicola1 aGarcia-León, Javier1 aNavarro-Marí, Jose, M1 aCamacho-Martinez, Pedro1 aMerino-Diaz, Laura1 ade Salazar, Adolfo1 aViñuela, Laura1 aLepe, Jose, A1 aGarcía, Federico1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/assessing-impact-sars-cov-2-lineages-and-mutations-patient-survival02967nas a2200445   4500008004100000022001400041245010400055210006900159260001600228490000700244520152100251653001901772653001301791653001101804653003201815653001501847653002901862653001901891653002401910100002601934700002201960700002801982700003002010700002802040700002702068700002702095700003002122700002802152700002202180700002002202700001602222700001902238700002802257700002202285700001602307700002402323700002402347700002202371856012802393       2022                        eng d  a1422-006700aEndoglin and MMP14 Contribute to Ewing Sarcoma Spreading by Modulation of Cell-Matrix Interactions.0 aEndoglin and MMP14 Contribute to Ewing Sarcoma Spreading by Modu  c2022 Aug 040 v233 a<p>Endoglin (ENG) is a mesenchymal stem cell (MSC) marker typically expressed by active endothelium. This transmembrane glycoprotein is shed by matrix metalloproteinase 14 (MMP14). Our previous work demonstrated potent preclinical activity of first-in-class anti-ENG antibody-drug conjugates as a nascent strategy to eradicate Ewing sarcoma (ES), a devastating rare bone/soft tissue cancer with a putative MSC origin. We also defined a correlation between ENG and MMP14 expression in ES. Herein, we show that ENG expression is significantly associated with a dismal prognosis in a large cohort of ES patients. Moreover, both ENG/MMP14 are frequently expressed in primary ES tumors and metastasis. To deepen in their functional relevance in ES, we conducted transcriptomic and proteomic profiling of in vitro ES models that unveiled a key role of ENG and MMP14 in cell mechano-transduction. Migration and adhesion assays confirmed that loss of ENG disrupts actin filament assembly and filopodia formation, with a concomitant effect on cell spreading. Furthermore, we observed that ENG regulates cell-matrix interaction through activation of focal adhesion signaling and protein kinase C expression. In turn, loss of MMP14 contributed to a more adhesive phenotype of ES cells by modulating the transcriptional extracellular matrix dynamics. Overall, these results suggest that ENG and MMP14 exert a significant role in mediating correct spreading machinery of ES cells, impacting the aggressiveness of the disease.</p>10aBone Neoplasms10aEndoglin10aHumans10aMatrix Metalloproteinase 1410aProteomics10aReceptors, Growth Factor10aSarcoma, Ewing10aSignal Transduction1 aPuerto-Camacho, Pilar1 aDiaz-Martin, Juan1 aOlmedo-Pelayo, Joaquín1 aBolado-Carrancio, Alfonso1 aSalguero-Aranda, Carmen1 aJordán-Pérez, Carmen1 aEsteban-Medina, Marina1 aAlamo-Alvarez, Inmaculada1 aDelgado-Bellido, Daniel1 aLobo-Selma, Laura1 aDopazo, Joaquin1 aSastre, Ana1 aAlonso, Javier1 aGrünewald, Thomas, G P1 aBernabeu, Carmelo1 aByron, Adam1 aBrunton, Valerie, G1 aAmaral, Ana, Teresa1 ade Alava, Enrique  uhttp://clinbioinfosspa.es/content/endoglin-and-mmp14-contribute-ewing-sarcoma-spreading-modulation-cell-matrix-interactions02333nas a2200373   4500008004100000022001400041245009100055210006900146260001600215300000800231490000700239520108200246653002401328653002601352653002301378653001101401100003001412700002901442700002801471700002801499700003701527700002401564700003101588700001801619700002701637700002501664700003101689700002401720700002001744700002601764700003201790700002501822856011201847       2021                        eng d  a1471-210500aA comprehensive database for integrated analysis of omics data in autoimmune diseases.0 acomprehensive database for integrated analysis of omics data in   c2021 Jun 24  a3430 v223 a<p><b>BACKGROUND: </b>Autoimmune diseases are heterogeneous pathologies with difficult diagnosis and few therapeutic options. In the last decade, several omics studies have provided significant insights into the molecular mechanisms of these diseases. Nevertheless, data from different cohorts and pathologies are stored independently in public repositories and a unified resource is imperative to assist researchers in this field.</p><p><b>RESULTS: </b>Here, we present Autoimmune Diseases Explorer ( https://adex.genyo.es ), a database that integrates 82 curated transcriptomics and methylation studies covering 5609 samples for some of the most common autoimmune diseases. The database provides, in an easy-to-use environment, advanced data analysis and statistical methods for exploring omics datasets, including meta-analysis, differential expression or pathway analysis.</p><p><b>CONCLUSIONS: </b>This is the first omics database focused on autoimmune diseases. This resource incorporates homogeneously processed data to facilitate integrative analyses among studies.</p>10aAutoimmune Diseases10aComputational Biology10aDatabases, Factual10aHumans1 aMartorell-Marugán, Jordi1 aLópez-Domínguez, Raúl1 aGarcía-Moreno, Adrián1 aToro-Domínguez, Daniel1 aVillatoro-García, Juan, Antonio1 aBarturen, Guillermo1 aMartín-Gómez, Adoración1 aTroule, Kevin1 aGómez-López, Gonzalo1 aAl-Shahrour, Fátima1 aGonzález-Rumayor, Víctor1 aPeña-Chilet, Maria1 aDopazo, Joaquin1 aSaez-Rodriguez, Julio1 aAlarcón-Riquelme, Marta, E1 aCarmona-Sáez, Pedro  uhttp://clinbioinfosspa.es/content/comprehensive-database-integrated-analysis-omics-data-autoimmune-diseases07188nas a2202077   4500008004100000022001400041245010000055210006900155260001200224300001100236490000700247520130900254653002101563653002601584653002201610653001301632653001401645653001601659653002301675653003101698653003201729653001101761653002301772653002201795653002101817653001601838653003601854653001801890653003201908653001501940653002401955653001301979653002601992653001902018100002302037700001902060700002202079700002102101700001802122700002702140700001902167700002602186700002602212700001802238700001902256700001702275700002202292700002102314700001902335700002902354700001802383700001602401700002902417700001802446700002302464700002202487700002002509700002002529700002702549700002102576700001702597700001802614700002402632700002102656700001602677700002102693700001902714700002302733700002302756700002002779700001702799700001902816700002402835700002102859700002402880700001702904700002302921700002402944700001902968700002002987700001903007700001903026700002903045700002303074700002003097700001703117700001803134700002403152700003303176700002003209700002003229700001603249700001503265700001803280700001903298700002603317700002703343700002003370700002403390700001803414700002403432700002203456700002203478700001903500700002003519700002103539700001803560700001503578700002203593700002303615700001703638700001903655700002403674700001703698700001803715700001703733700002303750700001803773700001803791700002303809700002103832700001703853700002203870700002003892700001803912700001803930700002303948700002103971700002503992700001804017700002004035700001704055700001904072700001704091700002104108700002504129700002704154700002404181700001604205700002104221700002504242700001704267700002004284700001804304700002504322700002404347700002304371700002104394700001904415700002204434700001804456700001604474700002204490700002004512700001804532700002504550700001904575700002204594700002404616700002304640700002004663700002304683700002204706700002304728700002304751700002604774700002004800700002204820700002004842700002304862700002104885700001804906700002404924710003504948856012704983       2021                        eng d  a1744-429200aCOVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms.0 aCOVID19 Disease Map a computational knowledge repository of viru  c2021 10  ae103870 v173 a<p>We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.</p>10aAntiviral Agents10aComputational Biology10aComputer Graphics10aCOVID-1910aCytokines10aData Mining10aDatabases, Factual10aGene Expression Regulation10aHost Microbial Interactions10aHumans10aImmunity, Cellular10aImmunity, Humoral10aImmunity, Innate10aLymphocytes10aMetabolic Networks and Pathways10aMyeloid Cells10aProtein Interaction Mapping10aSARS-CoV-210aSignal Transduction10aSoftware10aTranscription Factors10aViral Proteins1 aOstaszewski, Marek1 aNiarakis, Anna1 aMazein, Alexander1 aKuperstein, Inna1 aPhair, Robert1 aOrta-Resendiz, Aurelio1 aSingh, Vidisha1 aAghamiri, Sara, Sadat1 aAcencio, Marcio, Luis1 aGlaab, Enrico1 aRuepp, Andreas1 aFobo, Gisela1 aMontrone, Corinna1 aBrauner, Barbara1 aFrishman, Goar1 aGómez, Luis, Cristóbal1 aSomers, Julia1 aHoch, Matti1 aGupta, Shailendra, Kumar1 aScheel, Julia1 aBorlinghaus, Hanna1 aCzauderna, Tobias1 aSchreiber, Falk1 aMontagud, Arnau1 ade Leon, Miguel, Ponce1 aFunahashi, Akira1 aHiki, Yusuke1 aHiroi, Noriko1 aYamada, Takahiro, G1 aDräger, Andreas1 aRenz, Alina1 aNaveez, Muhammad1 aBocskei, Zsolt1 aMessina, Francesco1 aBörnigen, Daniela1 aFergusson, Liam1 aConti, Marta1 aRameil, Marius1 aNakonecnij, Vanessa1 aVanhoefer, Jakob1 aSchmiester, Leonard1 aWang, Muying1 aAckerman, Emily, E1 aShoemaker, Jason, E1 aZucker, Jeremy1 aOxford, Kristie1 aTeuton, Jeremy1 aKocakaya, Ebru1 aSummak, Gökçe, Yağmur1 aHanspers, Kristina1 aKutmon, Martina1 aCoort, Susan1 aEijssen, Lars1 aEhrhart, Friederike1 aRex, Devasahayam, Arokia Bal1 aSlenter, Denise1 aMartens, Marvin1 aPham, Nhung1 aHaw, Robin1 aJassal, Bijay1 aMatthews, Lisa1 aOrlic-Milacic, Marija1 aRibeiro, Andrea, Senff1 aRothfels, Karen1 aShamovsky, Veronica1 aStephan, Ralf1 aSevilla, Cristoffer1 aVarusai, Thawfeek1 aRavel, Jean-Marie1 aFraser, Rupsha1 aOrtseifen, Vera1 aMarchesi, Silvia1 aGawron, Piotr1 aSmula, Ewa1 aHeirendt, Laurent1 aSatagopam, Venkata1 aWu, Guanming1 aRiutta, Anders1 aGolebiewski, Martin1 aOwen, Stuart1 aGoble, Carole1 aHu, Xiaoming1 aOverall, Rupert, W1 aMaier, Dieter1 aBauch, Angela1 aGyori, Benjamin, M1 aBachman, John, A1 aVega, Carlos1 aGrouès, Valentin1 aVazquez, Miguel1 aPorras, Pablo1 aLicata, Luana1 aIannuccelli, Marta1 aSacco, Francesca1 aNesterova, Anastasia1 aYuryev, Anton1 ade Waard, Anita1 aTurei, Denes1 aLuna, Augustin1 aBabur, Ozgun1 aSoliman, Sylvain1 aValdeolivas, Alberto1 aEsteban-Medina, Marina1 aPeña-Chilet, Maria1 aRian, Kinza1 aHelikar, Tomáš1 aPuniya, Bhanwar, Lal1 aModos, Dezso1 aTreveil, Agatha1 aOlbei, Marton1 aDe Meulder, Bertrand1 aBallereau, Stephane1 aDugourd, Aurélien1 aNaldi, Aurélien1 aNoël, Vincent1 aCalzone, Laurence1 aSander, Chris1 aDemir, Emek1 aKorcsmaros, Tamas1 aFreeman, Tom, C1 aAugé, Franck1 aBeckmann, Jacques, S1 aHasenauer, Jan1 aWolkenhauer, Olaf1 aWilighagen, Egon, L1 aPico, Alexander, R1 aEvelo, Chris, T1 aGillespie, Marc, E1 aStein, Lincoln, D1 aHermjakob, Henning1 aD'Eustachio, Peter1 aSaez-Rodriguez, Julio1 aDopazo, Joaquin1 aValencia, Alfonso1 aKitano, Hiroaki1 aBarillot, Emmanuel1 aAuffray, Charles1 aBalling, Rudi1 aSchneider, Reinhard1 aCOVID-19 Disease Map Community  uhttp://clinbioinfosspa.es/content/covid19-disease-map-computational-knowledge-repository-virus-host-interaction-mechanisms03503nas a2200709   4500008004100000022001400041245008200055210006900137260001500206300001600221490000700237520139500244653001201639653002301651653001801674653002301692653001001715653001901725653002201744653002501766653001801791653001301809653001101822653001301833653002301846653001301869653001001882100002401892700001801916700002601934700002501960700002101985700002102006700002602027700002002053700002902073700002302102700002902125700002602154700002002180700002702200700002702227700001802254700001902272700003002291700001802321700003402339700001902373700002902392700002702421700001902448700002502467700001702492700002802509700002802537700001902565700002202584700001902606700002002625710004302645856010502688       2021                        eng d  a1362-496200aCSVS, a crowdsourcing database of the Spanish population genetic variability.0 aCSVS a crowdsourcing database of the Spanish population genetic   c2021 01 08  aD1130-D11370 v493 a<p>The knowledge of the genetic variability of the local population is of utmost importance in personalized medicine and has been revealed as a critical factor for the discovery of new disease variants. Here, we present the Collaborative Spanish Variability Server (CSVS), which currently contains more than 2000 genomes and exomes of unrelated Spanish individuals. This database has been generated in a collaborative crowdsourcing effort collecting sequencing data produced by local genomic projects and for other purposes. Sequences have been grouped by ICD10 upper categories. A web interface allows querying the database removing one or more ICD10 categories. In this way, aggregated counts of allele frequencies of the pseudo-control Spanish population can be obtained for diseases belonging to the category removed. Interestingly, in addition to pseudo-control studies, some population studies can be made, as, for example, prevalence of pharmacogenomic variants, etc. In addition, this genomic data has been used to define the first Spanish Genome Reference Panel (SGRP1.0) for imputation. This is the first local repository of variability entirely produced by a crowdsourcing effort and constitutes an example for future initiatives to characterize local variability worldwide. CSVS is also part of the GA4GH Beacon network. CSVS can be accessed at: http://csvs.babelomics.org/.</p>10aAlleles10aChromosome Mapping10aCrowdsourcing10aDatabases, Genetic10aExome10aGene Frequency10aGenetic Variation10aGenetics, Population10aGenome, Human10aGenomics10aHumans10aInternet10aPrecision Medicine10aSoftware10aSpain1 aPeña-Chilet, Maria1 aRoldán, Gema1 aPerez-Florido, Javier1 aOrtuno, Francisco, M1 aCarmona, Rosario1 aAquino, Virginia1 aLópez-López, Daniel1 aLoucera, Carlos1 aFernandez-Rueda, Jose, L1 aGallego, Asunción1 aGarcia-Garcia, Francisco1 aGonzález-Neira, Anna1 aPita, Guillermo1 aNúñez-Torres, Rocío1 aSantoyo-López, Javier1 aAyuso, Carmen1 aMinguez, Pablo1 aAvila-Fernandez, Almudena1 aCorton, Marta1 aMoreno-Pelayo, Miguel, Ángel1 aMorin, Matías1 aGallego-Martinez, Alvaro1 aLopez-Escamez, Jose, A1 aBorrego, Salud1 aAntiňolo, Guillermo1 aAmigo, Jorge1 aSalgado-Garrido, Josefa1 aPasalodos-Sanchez, Sara1 aMorte, Beatriz1 aCarracedo, Ángel1 aAlonso, Ángel1 aDopazo, Joaquin1 aSpanish Exome Crowdsourcing Consortium  uhttp://clinbioinfosspa.es/content/csvs-crowdsourcing-database-spanish-population-genetic-variability03228nas a2200613   4500008004100000022001400041245014900055210006900204260001200273300001200285490000800297520129600305653002101601653002601622653001301648653001001661653003101671653003201702653001101734653000901745653003301754653002101787653001901808653002201827653001301849653002601862653003401888653002701922100003001949700002701979700002802006700001702034700001902051700001902070700002102089700002902110700002202139700001902161700002402180700002202204700002102226700001902247700002102266700002202287700001702309700001902326700002002345700002602365700003002391700001902421700002602440700001902466856012902485       2021                        eng d  a1552-483300aDe novo small deletion affecting transcription start site of short isoform of AUTS2 gene in a patient with syndromic neurodevelopmental defects.0 aDe novo small deletion affecting transcription start site of sho  c2021 03  a877-8830 v1853 a<p>Disruption of the autism susceptibility candidate 2 (AUTS2) gene through genomic rearrangements, copy number variations (CNVs), and intragenic deletions and mutations, has been recurrently involved in syndromic forms of developmental delay and intellectual disability, known as AUTS2 syndrome. The AUTS2 gene plays an important role in regulation of neuronal migration, and when altered, associates with a variable phenotype from severely to mildly affected patients. The more severe phenotypes significantly correlate with the presence of defects affecting the C-terminus part of the gene. This article reports a new patient with a syndromic neurodevelopmental disorder, who presents a deletion of 30 nucleotides in the exon 9 of the AUTS2 gene. Importantly, this deletion includes the transcription start site for the AUTS2 short transcript isoform, which has an important role in brain development. Gene expression analysis of AUTS2 full-length and short isoforms revealed that the deletion found in this patient causes a remarkable reduction in the expression level, not only of the short isoform, but also of the full AUTS2 transcripts. This report adds more evidence for the role of mutated AUTS2 short transcripts in the development of a severe phenotype in the AUTS2 syndrome.</p>10aChild, Preschool10aCytoskeletal Proteins10aDwarfism10aExons10aGene Expression Regulation10aGenetic Association Studies10aHumans10aMale10aNeurodevelopmental Disorders10aProtein Isoforms10aRNA, Messenger10aSequence Deletion10aSyndrome10aTranscription Factors10aTranscription Initiation Site10aTranscription, Genetic1 aMartinez-Delgado, Beatriz1 aLopez-Martin, Estrella1 aLara-Herguedas, Julián1 aMonzon, Sara1 aCuesta, Isabel1 aJuliá, Miguel1 aAquino, Virginia1 aRodriguez-Martin, Carlos1 aDamian, Alejandra1 aGonzalo, Irene1 aGomez-Mariano, Gema1 aBaladron, Beatriz1 aCazorla, Rosario1 aIglesias, Gema1 aRoman, Enriqueta1 aRos, Purificacion1 aTutor, Pablo1 aMellor, Susana1 aJimenez, Carlos1 aCabrejas, Maria, Jose1 aGonzalez-Vioque, Emiliano1 aAlonso, Javier1 aBermejo-Sánchez, Eva1 aPosada, Manuel  uhttp://clinbioinfosspa.es/content/de-novo-small-deletion-affecting-transcription-start-site-short-isoform-auts2-gene-patient01023nas a2200313   4500008004100000022001400041245008100055210006900136260001200205300001400217490000700231653001500238653002600253653002400279653001100303653002300314653002000337653003200357100001500389700002000404700002600424700001700450700002400467700002100491700002600512700002500538710004000563856010600603       2021                        eng d  a1548-710500aDOME: recommendations for supervised machine learning validation in biology.0 aDOME recommendations for supervised machine learning validation   c2021 10  a1122-11270 v1810aAlgorithms10aComputational Biology10aGuidelines as Topic10aHumans10aModels, Biological10aResearch Design10aSupervised Machine Learning1 aWalsh, Ian1 aFishman, Dmytro1 aGarcia-Gasulla, Dario1 aTitma, Tiina1 aPollastri, Gianluca1 aHarrow, Jennifer1 aPsomopoulos, Fotis, E1 aTosatto, Silvio, C E1 aELIXIR Machine Learning Focus Group  uhttp://clinbioinfosspa.es/content/dome-recommendations-supervised-machine-learning-validation-biology02196nas a2200325   4500008004100000022001400041245010300055210006900158260001300227300001400240490000700254520111400261653001201375653002201387653003501409653002801444653001301472653001101485653001801496653001801514653001901532100003501551700002501586700002901611700002301640700002901663700002401692700002601716856012801742       2021                        eng d  a1432-085100aImmunotherapy in nonsmall-cell lung cancer: current status and future prospects for liquid biopsy.0 aImmunotherapy in nonsmallcell lung cancer current status and fut  c2021 May  a1177-11880 v703 a<p>Immunotherapy has been one of the great advances in the recent years for the treatment of advanced tumors, with nonsmall-cell lung cancer (NSCLC) being one of the cancers that has benefited most from this approach. Currently, the only validated companion diagnostic test for first-line immunotherapy in metastatic NSCLC patients is testing for programmed death ligand 1 (PD-L1) expression in tumor tissues. However, not all patients experience an effective response with the established selection criteria and immune checkpoint inhibitors (ICIs). Liquid biopsy offers a noninvasive opportunity to monitor disease in patients with cancer and identify those who would benefit the most from immunotherapy. This review focuses on the use of liquid biopsy in immunotherapy treatment of NSCLC patients. Circulating tumor cells (CTCs), cell-free DNA (cfDNA) and exosomes are promising tools for developing new biomarkers. We discuss the current application and future implementation of these parameters to improve therapeutic decision-making and identify the patients who will benefit most from immunotherapy.</p>10aAnimals10aBiomarkers, Tumor10aCarcinoma, Non-Small-Cell Lung10aCell-Free Nucleic Acids10aExosomes10aHumans10aImmunotherapy10aLiquid Biopsy10aLung Neoplasms1 aBrozos-Vázquez, Elena, María1 aDíaz-Peña, Roberto1 aGarcía-González, Jorge1 aLeón-Mateos, Luis1 aMondelo-Macía, Patricia1 aPeña-Chilet, Maria1 aLópez-López, Rafael  uhttp://clinbioinfosspa.es/content/immunotherapy-nonsmall-cell-lung-cancer-current-status-and-future-prospects-liquid-biopsy02756nas a2200385   4500008004100000022001400041245015900055210006900214260001500283300001000298490000700308520150900315653001601824653001301840653001101853653001101864653002601875653000901901653002601910653001001936653002201946653001401968100002001982700002402002700002702026700003102053700002102084700002602105700002902131700001802160700002002178700002002198700002802218856012402246       2021                        eng d  a2045-232200aReal world evidence of calcifediol or vitamin D prescription and mortality rate of COVID-19 in a retrospective cohort of hospitalized Andalusian patients.0 aReal world evidence of calcifediol or vitamin D prescription and  c2021 12 03  a233800 v113 a<p>COVID-19 is a major worldwide health problem because of acute respiratory distress syndrome, and mortality. Several lines of evidence have suggested a relationship between the vitamin D endocrine system and severity of COVID-19. We present a survival study on a retrospective cohort of 15,968 patients, comprising all COVID-19 patients hospitalized in Andalusia between January and November 2020. Based on a central registry of electronic health records (the Andalusian Population Health Database, BPS), prescription of vitamin D or its metabolites within 15-30 days before hospitalization were recorded. The effect of prescription of vitamin D (metabolites) for other indication previous to the hospitalization was studied with respect to patient survival. Kaplan-Meier survival curves and hazard ratios support an association between prescription of these metabolites and patient survival. Such association was stronger for calcifediol (Hazard Ratio, HR = 0.67, with 95% confidence interval, CI, of [0.50-0.91]) than for cholecalciferol (HR = 0.75, with 95% CI of [0.61-0.91]), when prescribed 15 days prior hospitalization. Although the relation is maintained, there is a general decrease of this effect when a longer period of 30 days prior hospitalization is considered (calcifediol HR = 0.73, with 95% CI [0.57-0.95] and cholecalciferol HR = 0.88, with 95% CI [0.75, 1.03]), suggesting that association was stronger when the prescription was closer to the hospitalization.</p>10aCalcifediol10aCOVID-1910aFemale10aHumans10aKaplan-Meier Estimate10aMale10aRetrospective Studies10aSpain10aSurvival Analysis10aVitamin D1 aLoucera, Carlos1 aPeña-Chilet, Maria1 aEsteban-Medina, Marina1 aMuñoyerro-Muñiz, Dolores1 aVillegas, Román1 aLópez-Miranda, José1 aRodríguez-Baño, Jesús1 aTúnez, Isaac1 aBouillon, Roger1 aDopazo, Joaquin1 aGomez, Jose, Manuel Que  uhttp://clinbioinfosspa.es/content/real-world-evidence-calcifediol-or-vitamin-d-prescription-and-mortality-rate-covid-1905404nas a2201477   4500008004100000022001400041245007800055210006900133260001200202300001400214490000700228520122900235653002601464653001401490653001101504653001501515653003501530653002001565653003801585100001901623700001901642700001801661700002301679700002401702700002301726700002101749700002801770700001801798700002501816700002401841700002701865700001801892700002301910700002001933700001501953700002201968700002001990700002702010700002102037700002202058700001802080700001902098700002702117700002002144700001902164700002002183700002102203700001702224700002102241700002302262700002002285700002202305700002002327700001802347700002302365700001802388700002102406700002602427700001902453700001702472700001802489700002402507700001902531700001602550700001702566700001602583700002102599700002102620700002102641700002102662700002202683700002202705700002102727700001602748700001702764700001502781700002102796700001702817700002402834700002202858700002002880700002402900700001802924700001602942700002302958700002102981700002403002700001703026700002603043700002403069700002503093700002403118700002203142700002103164700001703185700001903202700001803221700001803239700001303257700001703270700001603287700001903303700002703322700002003349700001703369700002203386700001903408700001903427700002603446700001903472700002903491700002103520700001603541700002203557700001603579700002003595700002403615700001903639700002403658700002203682700002003704700001803724710003303742710004903775856010203824       2021                        eng d  a1546-170X00aReporting guidelines for human microbiome research: the STORMS checklist.0 aReporting guidelines for human microbiome research the STORMS ch  c2021 11  a1885-18920 v273 a<p>The particularly interdisciplinary nature of human microbiome research makes the organization and reporting of results spanning epidemiology, biology, bioinformatics, translational medicine and statistics a challenge. Commonly used reporting guidelines for observational or genetic epidemiology studies lack key features specific to microbiome studies. Therefore, a multidisciplinary group of microbiome epidemiology researchers adapted guidelines for observational and genetic studies to culture-independent human microbiome studies, and also developed new reporting elements for laboratory, bioinformatics and statistical analyses tailored to microbiome studies. The resulting tool, called 'Strengthening The Organization and Reporting of Microbiome Studies' (STORMS), is composed of a 17-item checklist organized into six sections that correspond to the typical sections of a scientific publication, presented as an editable table for inclusion in supplementary materials. The STORMS checklist provides guidance for concise and complete reporting of microbiome studies that will facilitate manuscript preparation, peer review, and reader comprehension of publications and comparative analysis of published results.</p>10aComputational Biology10aDysbiosis10aHumans10aMicrobiota10aObservational Studies as Topic10aResearch Design10aTranslational Science, Biomedical1 aMirzayi, Chloe1 aRenson, Audrey1 aZohra, Fatima1 aElsafoury, Shaimaa1 aGeistlinger, Ludwig1 aKasselman, Lora, J1 aEckenrode, Kelly1 avan de Wijgert, Janneke1 aLoughman, Amy1 aMarques, Francine, Z1 aMacIntyre, David, A1 aArumugam, Manimozhiyan1 aAzhar, Rimsha1 aBeghini, Francesco1 aBergstrom, Kirk1 aBhatt, Ami1 aBisanz, Jordan, E1 aBraun, Jonathan1 aBravo, Hector, Corrada1 aBuck, Gregory, A1 aBushman, Frederic1 aCasero, David1 aClarke, Gerard1 aCollado, Maria, Carmen1 aCotter, Paul, D1 aCryan, John, F1 aDemmer, Ryan, T1 aDevkota, Suzanne1 aElinav, Eran1 aEscobar, Juan, S1 aFettweis, Jennifer1 aFinn, Robert, D1 aFodor, Anthony, A1 aForslund, Sofia1 aFranke, Andre1 aFurlanello, Cesare1 aGilbert, Jack1 aGrice, Elizabeth1 aHaibe-Kains, Benjamin1 aHandley, Scott1 aHerd, Pamela1 aHolmes, Susan1 aJacobs, Jonathan, P1 aKarstens, Lisa1 aKnight, Rob1 aKnights, Dan1 aKoren, Omry1 aKwon, Douglas, S1 aLangille, Morgan1 aLindsay, Brianna1 aMcGovern, Dermot1 aMcHardy, Alice, C1 aMcWeeney, Shannon1 aMueller, Noel, T1 aNezi, Luigi1 aOlm, Matthew1 aPalm, Noah1 aPasolli, Edoardo1 aRaes, Jeroen1 aRedinbo, Matthew, R1 aRühlemann, Malte1 aSartor, Balfour1 aSchloss, Patrick, D1 aSchriml, Lynn1 aSegal, Eran1 aShardell, Michelle1 aSharpton, Thomas1 aSmirnova, Ekaterina1 aSokol, Harry1 aSonnenburg, Justin, L1 aSrinivasan, Sujatha1 aThingholm, Louise, B1 aTurnbaugh, Peter, J1 aUpadhyay, Vaibhav1 aWalls, Ramona, L1 aWilmes, Paul1 aYamada, Takuji1 aZeller, Georg1 aZhang, Mingyu1 aZhao, Ni1 aZhao, Liping1 aBao, Wenjun1 aCulhane, Aedin1 aDevanarayan, Viswanath1 aDopazo, Joaquin1 aFan, Xiaohui1 aFischer, Matthias1 aJones, Wendell1 aKusko, Rebecca1 aMason, Christopher, E1 aMercer, Tim, R1 aSansone, Susanna-Assunta1 aScherer, Andreas1 aShi, Leming1 aThakkar, Shraddha1 aTong, Weida1 aWolfinger, Russ1 aHunter, Christopher1 aSegata, Nicola1 aHuttenhower, Curtis1 aDowd, Jennifer, B1 aJones, Heidi, E1 aWaldron, Levi1 aGenomic Standards Consortium1 aMassive Analysis and Quality Control Society  uhttp://clinbioinfosspa.es/content/reporting-guidelines-human-microbiome-research-storms-checklist03596nas a2200505   4500008004100000022001400041245013900055210006900194260001500263300000700278490000700285520188200292653001702174653002602191653001402217653003202231653000902263653001102272653001502283653001702298653003202315653002902347653001402376100003502390700003102425700003302456700002002489700001802509700002802527700003202555700002902587700003002616700002602646700001902672700003602691700002202727700002902749700002802778700003102806700002602837700002602863700003302889700004002922856012802962       2021                        eng d  a1528-365800aTaxonomic variations in the gut microbiome of gout patients with and without tophi might have a functional impact on urate metabolism.0 aTaxonomic variations in the gut microbiome of gout patients with  c2021 05 24  a500 v273 a<p><b>OBJECTIVE: </b>To evaluate the taxonomic composition of the gut microbiome in gout patients with and without tophi formation, and predict bacterial functions that might have an impact on urate metabolism.</p><p><b>METHODS: </b>Hypervariable V3-V4 regions of the bacterial 16S rRNA gene from fecal samples of gout patients with and without tophi (n = 33 and n = 25, respectively) were sequenced and compared to fecal samples from 53 healthy controls. We explored predictive functional profiles using bioinformatics in order to identify differences in taxonomy and metabolic pathways.</p><p><b>RESULTS: </b>We identified a microbiome characterized by the lowest richness and a higher abundance of Phascolarctobacterium, Bacteroides, Akkermansia, and Ruminococcus_gnavus_group genera in patients with gout without tophi when compared to controls. The Proteobacteria phylum and the Escherichia-Shigella genus were more abundant in patients with tophaceous gout than in controls. Fold change analysis detected nine genera enriched in healthy controls compared to gout groups (Bifidobacterium, Butyricicoccus, Oscillobacter, Ruminococcaceae_UCG_010, Lachnospiraceae_ND2007_group, Haemophilus, Ruminococcus_1, Clostridium_sensu_stricto_1, and Ruminococcaceae_UGC_013). We found that the core microbiota of both gout groups shared Bacteroides caccae, Bacteroides stercoris ATCC 43183, and Bacteroides coprocola DSM 17136. These bacteria might perform functions linked to one-carbon metabolism, nucleotide binding, amino acid biosynthesis, and purine biosynthesis. Finally, we observed differences in key bacterial enzymes involved in urate synthesis, degradation, and elimination.</p><p><b>CONCLUSION: </b>Our findings revealed that taxonomic variations in the gut microbiome of gout patients with and without tophi might have a functional impact on urate metabolism.</p>10aBiodiversity10aComputational Biology10aDysbiosis10aGastrointestinal Microbiome10aGout10aHumans10aMetagenome10ametagenomics10aProtein Interaction Mapping10aProtein Interaction Maps10aUric Acid1 aMéndez-Salazar, Eder, Orlando1 aVázquez-Mellado, Janitzia1 aCasimiro-Soriguer, Carlos, S1 aDopazo, Joaquin1 aCubuk, Cankut1 aZamudio-Cuevas, Yessica1 aFrancisco-Balderas, Adriana1 aMartínez-Flores, Karina1 aFernández-Torres, Javier1 aLozada-Pérez, Carlos1 aPineda, Carlos1 aSánchez-González, Austreberto1 aSilveira, Luis, H1 aBurguete-García, Ana, I1 aOrbe-Orihuela, Citlalli1 aLagunas-Martínez, Alfredo1 aVazquez-Gomez, Alonso1 aLópez-Reyes, Alberto1 aPalacios-González, Berenice1 aMartínez-Nava, Gabriela, Angélica  uhttp://clinbioinfosspa.es/content/taxonomic-variations-gut-microbiome-gout-patients-and-without-tophi-might-have-functional02115nas a2200409   4500008004100000022001400041245012500055210006900180260001200249300001300261490000700274520080500281653001501086653002101101653002601122653002301148653003001171653001301201653004201214653001101256653002401267653001301291653001201304653002401316653001301340653001801353653002701371653001301398100003101411700002601442700002501468700002401493700002001517700002201537700002001559856012601579       2021                        eng d  a1553-735800aA versatile workflow to integrate RNA-seq genomic and transcriptomic data into mechanistic models of signaling pathways.0 aversatile workflow to integrate RNAseq genomic and transcriptomi  c2021 02  ae10087480 v173 a<p>MIGNON is a workflow for the analysis of RNA-Seq experiments, which not only efficiently manages the estimation of gene expression levels from raw sequencing reads, but also calls genomic variants present in the transcripts analyzed. Moreover, this is the first workflow that provides a framework for the integration of transcriptomic and genomic data based on a mechanistic model of signaling pathway activities that allows a detailed biological interpretation of the results, including a comprehensive functional profiling of cell activity. MIGNON covers the whole process, from reads to signaling circuit activity estimations, using state-of-the-art tools, it is easy to use and it is deployable in different computational environments, allowing an optimized use of the resources available.</p>10aAlgorithms10aCell Line, Tumor10aComputational Biology10aDatabases, Factual10aGene Expression Profiling10aGenomics10aHigh-Throughput Nucleotide Sequencing10aHumans10aModels, Theoretical10amutation10aRNA-seq10aSignal Transduction10aSoftware10aTranscriptome10awhole exome sequencing10aWorkflow1 aGarrido-Rodriguez, Martín1 aLópez-López, Daniel1 aOrtuno, Francisco, M1 aPeña-Chilet, Maria1 aMuñoz, Eduardo1 aCalzado, Marco, A1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/versatile-workflow-integrate-rna-seq-genomic-and-transcriptomic-data-mechanistic-models03640nas a2200565   4500008004100000022001400041245014000055210006900195260001300264300001200277490000700289520189600296653004202192653003102234653001502265653001902280653002002299653002402319653001902343653003002362653003202392653001502424653001902439653002802458653001002486653001102496653001602507653004402523653001402567653003602581653002702617100002102644700003102665700001502696700001402711700001502725700002202740700001602762700001202778700002302790700001402813700001302827700001902840700002402859700001502883700001402898700001902912700001502931856012802946       2020                        eng d  a1469-069100aAssociation of a single nucleotide polymorphism in the ubxn6 gene with long-term non-progression phenotype in HIV-positive individuals.0 aAssociation of a single nucleotide polymorphism in the ubxn6 gen  c2020 Jan  a107-1140 v263 a<p><b>OBJECTIVES: </b>The long-term non-progressors (LTNPs) are a heterogeneous group of HIV-positive individuals characterized by their ability to maintain high CD4 T-cell counts and partially control viral replication for years in the absence of antiretroviral therapy. The present study aims to identify host single nucleotide polymorphisms (SNPs) associated with non-progression in a cohort of 352 individuals.</p><p><b>METHODS: </b>DNA microarrays and exome sequencing were used for genotyping about 240 000 functional polymorphisms throughout more than 20 000 human genes. The allele frequencies of 85 LTNPs were compared with a control population. SNPs associated with LTNPs were confirmed in a population of typical progressors. Functional analyses in the affected gene were carried out through knockdown experiments in HeLa-P4, macrophages and dendritic cells.</p><p><b>RESULTS: </b>Several SNPs located within the major histocompatibility complex region previously related to LTNPs were confirmed in this new cohort. The SNP rs1127888 (UBXN6) surpassed the statistical significance of these markers after Bonferroni correction (q = 2.11 × 10). An uncommon allelic frequency of rs1127888 among LTNPs was confirmed by comparison with typical progressors and other publicly available populations. UBXN6 knockdown experiments caused an increase in CAV1 expression and its accumulation in the plasma membrane. In vitro infection of different cell types with HIV-1 replication-competent recombinant viruses caused a reduction of the viral replication capacity compared with their corresponding wild-type cells expressing UBXN6.</p><p><b>CONCLUSIONS: </b>A higher prevalence of Ala31Thr in UBXN6 was found among LTNPs within its N-terminal region, which is crucial for UBXN6/VCP protein complex formation. UBXN6 knockdown affected CAV1 turnover and HIV-1 replication capacity.</p>10aAdaptor Proteins, Vesicular Transport10aAutophagy-Related Proteins10aCaveolin 110aCohort Studies10aDendritic Cells10aDisease Progression10aGene Frequency10aGene Knockdown Techniques10aGenetic Association Studies10aHeLa Cells10aHIV Infections10aHIV Long-Term Survivors10aHIV-110aHumans10aMacrophages10aOligonucleotide Array Sequence Analysis10aPhenotype10aPolymorphism, Single Nucleotide10awhole exome sequencing1 aDíez-Fuertes, F1 aDe La Torre-Tarazona, H, E1 aCalonge, E1 aPernas, M1 aBermejo, M1 aGarcía-Pérez, J1 aÁlvarez, A1 aCapa, L1 aGarcía-García, F1 aSaumoy, M1 aRiera, M1 aBoland-Auge, A1 aLópez-Galíndez, C1 aLathrop, M1 aDopazo, J1 aSakuntabhai, A1 aAlcamí, J  uhttp://clinbioinfosspa.es/content/association-single-nucleotide-polymorphism-ubxn6-gene-long-term-non-progression-phenotype02932nas a2200613   4500008004100000022001400041245012600055210006900181260001500250300001500265490000700280520120500287653001801492653001101510653001301521653001101534653002101545653000901566653001401575653002001589653001301609653001501622653001801637100001301655700002401668700001201692700001701704700001601721700001701737700001601754700001601770700001201786700001401798700001601812700001501828700002101843700002101864700002201885700001501907700002301922700002101945700002101966700001601987700001602003700002102019700002502040700001902065700001702084700001402101700001802115700002602133710003102159856012802190       2020                        eng d  a2405-472000aCommunity Assessment of the Predictability of Cancer Protein and Phosphoprotein Levels from Genomics and Transcriptomics.0 aCommunity Assessment of the Predictability of Cancer Protein and  c2020 08 26  a186-195.e90 v113 a<p>Cancer is driven by genomic alterations, but the processes causing this disease are largely performed by proteins. However, proteins are harder and more expensive to measure than genes and transcripts. To catalyze developments of methods to infer protein levels from other omics measurements, we leveraged crowdsourcing via the NCI-CPTAC DREAM proteogenomic challenge. We asked for methods to predict protein and phosphorylation levels from genomic and transcriptomic data in cancer patients. The best performance was achieved by an ensemble of models, including as predictors transcript level of the corresponding genes, interaction between genes, conservation across tumor types, and phosphosite proximity for phosphorylation prediction. Proteins from metabolic pathways and complexes were the best and worst predicted, respectively. The performance of even the best-performing model was modest, suggesting that many proteins are strongly regulated through translational control and degradation. Our results set a reference for the limitations of computational inference in proteogenomics. A record of this paper's transparent peer review process is included in the Supplemental Information.</p>10aCrowdsourcing10aFemale10aGenomics10aHumans10aMachine Learning10aMale10aNeoplasms10aPhosphoproteins10aProteins10aProteomics10aTranscriptome1 aYang, Mi1 aPetralia, Francesca1 aLi, Zhi1 aLi, Hongyang1 aMa, Weiping1 aSong, Xiaoyu1 aKim, Sunkyu1 aLee, Heewon1 aYu, Han1 aLee, Bora1 aBae, Seohui1 aHeo, Eunji1 aKaczmarczyk, Jan1 aStępniak, Piotr1 aWarchoł, Michał1 aYu, Thomas1 aCalinawan, Anna, P1 aBoutros, Paul, C1 aPayne, Samuel, H1 aReva, Boris1 aBoja, Emily1 aRodriguez, Henry1 aStolovitzky, Gustavo1 aGuan, Yuanfang1 aKang, Jaewoo1 aWang, Pei1 aFenyö, David1 aSaez-Rodriguez, Julio1 aNCI-CPTAC-DREAM Consortium  uhttp://clinbioinfosspa.es/content/community-assessment-predictability-cancer-protein-and-phosphoprotein-levels-genomics-and01793nas a2200577   4500008004100000022001400041245011100055210006900166260001500235300000800250490000600258653002000264653002600284653002700310653001300337653002300350653003200373653003100405653001100436653003000447653002300477653001400500653002100514653001500535100002300550700002200573700002300595700002100618700001900639700002300658700002300681700002500704700002000729700001900749700002000768700002100788700001600809700002200825700002200847700002300869700002000892700002700912700002300939700002200962700002100984700002001005700002101025700001801046700002401064856012701088       2020                        eng d  a2052-446300aCOVID-19 Disease Map, building a computational repository of SARS-CoV-2 virus-host interaction mechanisms.0 aCOVID19 Disease Map building a computational repository of SARSC  c2020 05 05  a1360 v710aBetacoronavirus10aComputational Biology10aCoronavirus Infections10aCOVID-1910aDatabases, Factual10aHost Microbial Interactions10aHost-Pathogen Interactions10aHumans10aInternational Cooperation10aModels, Biological10aPandemics10aPneumonia, Viral10aSARS-CoV-21 aOstaszewski, Marek1 aMazein, Alexander1 aGillespie, Marc, E1 aKuperstein, Inna1 aNiarakis, Anna1 aHermjakob, Henning1 aPico, Alexander, R1 aWillighagen, Egon, L1 aEvelo, Chris, T1 aHasenauer, Jan1 aSchreiber, Falk1 aDräger, Andreas1 aDemir, Emek1 aWolkenhauer, Olaf1 aFurlong, Laura, I1 aBarillot, Emmanuel1 aDopazo, Joaquin1 aOrta-Resendiz, Aurelio1 aMessina, Francesco1 aValencia, Alfonso1 aFunahashi, Akira1 aKitano, Hiroaki1 aAuffray, Charles1 aBalling, Rudi1 aSchneider, Reinhard  uhttp://clinbioinfosspa.es/content/covid-19-disease-map-building-computational-repository-sars-cov-2-virus-host-interaction01082nas a2200313   4500008004100000022001400041245014500055210006900200260001500269300000800284490000600292653002800298653001300326653002300339653001100362653002100373653003300394653003100427653001300458653001500471653002400486100002000510700002700530700001600557700002100573700002000594700002400614856013000638       2020                        eng d  a2059-363500aDrug repurposing for COVID-19 using machine learning and mechanistic models of signal transduction circuits related to SARS-CoV-2 infection.0 aDrug repurposing for COVID19 using machine learning and mechanis  c2020 12 11  a2900 v510aComputational Chemistry10aCOVID-1910adrug repositioning10aHumans10aMachine Learning10aMolecular Docking Simulation10aMolecular Targeted Therapy10aProteins10aSARS-CoV-210aSignal Transduction1 aLoucera, Carlos1 aEsteban-Medina, Marina1 aRian, Kinza1 aFalco, Matias, M1 aDopazo, Joaquin1 aPeña-Chilet, Maria  uhttp://clinbioinfosspa.es/content/drug-repurposing-covid-19-using-machine-learning-and-mechanistic-models-signal-transduction03120nas a2200673   4500008004100000022001400041245010800055210006900163260000900232490000600241520108900247653002601336653003101362653004201393653001101435100001901446700002101465700002001486700001901506700003301525700002701558700003501585700002001620700002201640700001201662700001801674700002201692700001301714700002101727700002001748700002101768700001801789700001801807700002601825700001801851700001601869700002401885700001801909700002101927700001701948700002701965700001801992700002302010700001902033700002702052700001402079700002302093700001702116700001902133700001502152700002202167700002102189700002202210700001702232700003202249700001802281700002402299856012302323       2020                        eng d  a2046-140200aThe ELIXIR Human Copy Number Variations Community: building bioinformatics infrastructure for research.0 aELIXIR Human Copy Number Variations Community building bioinform  c20200 v93 a<p>Copy number variations (CNVs) are major causative contributors both in the genesis of genetic diseases and human neoplasias. While "High-Throughput" sequencing technologies are increasingly becoming the primary choice for genomic screening analysis, their ability to efficiently detect CNVs is still heterogeneous and remains to be developed. The aim of this white paper is to provide a guiding framework for the future contributions of ELIXIR's recently established   with implications beyond human disease diagnostics and population genomics. This white paper is the direct result of a strategy meeting that took place in September 2018 in Hinxton (UK) and involved representatives of 11 ELIXIR Nodes. The meeting led to the definition of priority objectives and tasks, to address a wide range of CNV-related challenges ranging from detection and interpretation to sharing and training. Here, we provide suggestions on how to align these tasks within the ELIXIR Platforms strategy, and on how to frame the activities of this new ELIXIR Community in the international context.</p>10aComputational Biology10aDNA Copy Number Variations10aHigh-Throughput Nucleotide Sequencing10aHumans1 aSalgado, David1 aArmean, Irina, M1 aBaudis, Michael1 aBeltran, Sergi1 aCapella-Gutíerrez, Salvador1 aCarvalho-Silva, Denise1 aDel Angel, Victoria, Dominguez1 aDopazo, Joaquin1 aFurlong, Laura, I1 aGao, Bo1 aGarcia, Leyla1 aGerloff, Dietlind1 aGut, Ivo1 aGyenesei, Attila1 aHabermann, Nina1 aHancock, John, M1 aHanauer, Marc1 aHovig, Eivind1 aJohansson, Lennart, F1 aKeane, Thomas1 aKorbel, Jan1 aLauer, Katharina, B1 aLaurie, Steve1 aLeskošek, Brane1 aLloyd, David1 aMarqués-Bonet, Tomás1 aMei, Hailiang1 aMonostory, Katalin1 aPiñero, Janet1 aPoterlowicz, Krzysztof1 aRath, Ana1 aSamarakoon, Pubudu1 aSanz, Ferran1 aSaunders, Gary1 aSie, Daoud1 aSwertz, Morris, A1 aTsukanov, Kirill1 aValencia, Alfonso1 aVidak, Marko1 aGonzález, Cristina, Yenyxe1 aYlstra, Bauke1 aBéroud, Christophe  uhttp://clinbioinfosspa.es/content/elixir-human-copy-number-variations-community-building-bioinformatics-infrastructure01455nas a2200217   4500008004100000022001400041245006500055210006200120260001900182300001200201490000700213520073900220653002200959653001100981100003700992700002901029700003801058700003101096700002001127856009001147       2020                        spa d  a1578-128300a[Impact assessment on data protection in research projects].0 aImpact assessment on data protection in research projects  c2020 Sep - Oct  a521-5230 v343 a<p>Recent changes in European regulations for personal data protection still allow the use of health data for research purposes, but they have set the Impact Assessment on Data Protection as an instrument for reflection and risk analysis in the process of data processing. The publication of a guide for facilitates this impact assessment, although it is not directly applicable to research projects. Experience in a specific project is detailed, showing how the context of the treatment becomes relevant with respect to the data characteristics. Carrying out an impact assessment is an opportunity to ensure compliance with the principles of data protection in an increasingly complex environment with greater ethical challenges.</p>10aComputer Security10aHumans1 aGarcía-León, Francisco, Javier1 aVillegas-Portero, Román1 aGoicoechea-Salazar, Juan, Antonio1 aMuñoyerro-Muñiz, Dolores1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/impact-assessment-data-protection-research-projects02316nas a2200241   4500008004100000022001400041245014100055210006900196260001500265490000600280520146700286653001101753653004301764653001101807653000901818653001401827653002401841100001801865700001801883700002401901700002001925856012901945       2020                        eng d  a2073-440900aMechanistic Models of Signaling Pathways Reveal the Drug Action Mechanisms behind Gender-Specific Gene Expression for Cancer Treatments.0 aMechanistic Models of Signaling Pathways Reveal the Drug Action   c2020 06 290 v93 a<p>Despite the existence of differences in gene expression across numerous genes between males and females having been known for a long time, these have been mostly ignored in many studies, including drug development and its therapeutic use. In fact, the consequences of such differences over the disease mechanisms or the drug action mechanisms are completely unknown. Here we applied mechanistic mathematical models of signaling activity to reveal the ultimate functional consequences that gender-specific gene expression activities have over cell functionality and fate. Moreover, we also used the mechanistic modeling framework to simulate the drug interventions and unravel how drug action mechanisms are affected by gender-specific differential gene expression. Interestingly, some cancers have many biological processes significantly affected by these gender-specific differences (e.g., bladder or head and neck carcinomas), while others (e.g., glioblastoma or rectum cancer) are almost insensitive to them. We found that many of these gender-specific differences affect cancer-specific pathways or in physiological signaling pathways, also involved in cancer origin and development. Finally, mechanistic models have the potential to be used for finding alternative therapeutic interventions on the pathways targeted by the drug, which lead to similar results compensating the downstream consequences of gender-specific differences in gene expression.</p>10aFemale10aGene Expression Regulation, Neoplastic10aHumans10aMale10aNeoplasms10aSignal Transduction1 aCubuk, Cankut1 aCan, Fatma, E1 aPeña-Chilet, Maria1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/mechanistic-models-signaling-pathways-reveal-drug-action-mechanisms-behind-gender-specific03270nas a2200493   4500008004100000022001400041245012000055210006900175260001200244490000600256520175600262653001002018653000902028653004102037653001102078653001102089653000902100653001602109653001402125653001202139653001402151653001602165100002502181700001702206700002302223700002902246700002002275700002202295700002402317700002502341700002402366700002302390700002502413700002802438700002202466700001902488700002402507700002002531700002702551700002502578700002002603700002602623856012702649       2020                        eng d  a2051-142600aNivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial.0 aNivolumab and sunitinib combination in advanced soft tissue sarc  c2020 110 v83 a<p><b>BACKGROUND: </b>Sarcomas exhibit low expression of factors related to immune response, which could explain the modest activity of PD-1 inhibitors. A potential strategy to convert a cold into an inflamed microenvironment lies on a combination therapy. As tumor angiogenesis promotes immunosuppression, we designed a phase Ib/II trial to test the double inhibition of angiogenesis (sunitinib) and PD-1/PD-L1 axis (nivolumab).</p><p><b>METHODS: </b>This single-arm, phase Ib/II trial enrolled adult patients with selected subtypes of sarcoma. Phase Ib established two dose levels: level 0 with sunitinib 37.5 mg daily from day 1, plus nivolumab 3 mg/kg intravenously on day 15, and then every 2 weeks; and level -1 with sunitinib 37.5 mg on the first 14 days (induction) and then 25 mg per day plus nivolumab on the same schedule. The primary endpoint was to determine the recommended dose for phase II (phase I) and the 6-month progression-free survival rate, according to Response Evaluation Criteria in Solid Tumors 1.1 (phase II).</p><p><b>RESULTS: </b>From May 2017 to April 2019, 68 patients were enrolled: 16 in phase Ib and 52 in phase II. The recommended dose of sunitinib for phase II was 37.5 mg as induction and then 25 mg in combination with nivolumab. After a median follow-up of 17 months (4-26), the 6-month progression-free survival rate was 48% (95% CI 41% to 55%). The most common grade 3-4 adverse events included transaminitis (17.3%) and neutropenia (11.5%).</p><p><b>CONCLUSIONS: </b>Sunitinib plus nivolumab is an active scheme with manageable toxicity in the treatment of selected patients with advanced soft tissue sarcoma, with almost half of patients free of progression at 6 months. NCT03277924.</p>10aAdult10aAged10aAntineoplastic Agents, Immunological10aFemale10aHumans10aMale10aMiddle Aged10aNivolumab10aSarcoma10aSunitinib10aYoung Adult1 aMartin-Broto, Javier1 aHindi, Nadia1 aGrignani, Giovanni1 aMartinez-Trufero, Javier1 aRedondo, Andres1 aValverde, Claudia1 aStacchiotti, Silvia1 aLopez-Pousa, Antonio1 aD'Ambrosio, Lorenzo1 aGutierrez, Antonio1 aPerez-Vega, Herminia1 aEncinas-Tobajas, Victor1 ade Alava, Enrique1 aCollini, Paola1 aPeña-Chilet, Maria1 aDopazo, Joaquin1 aCarrasco-Garcia, Irene1 aLopez-Alvarez, Maria1 aMoura, David, S1 aLopez-Martin, Jose, A  uhttp://clinbioinfosspa.es/content/nivolumab-and-sunitinib-combination-advanced-soft-tissue-sarcomas-multicenter-single-arm05175nas a2201117   4500008004100000022001400041245011300055210006900168260001200237300001200249490000700261520174900268653001402017653003102031653001502062653002502077653001902102653005102121653001102172653002902183653003802212653001102250653000902261653002302270653003602293653002702329100002202356700001702378700002402395700002802419700003302447700002702480700001502507700002402522700002902546700002602575700002802601700001702629700002002646700002102666700001902687700002702706700001902733700002002752700002402772700003002796700001902826700002602845700002902871700001802900700002102918700002202939700003202961700002002993700002603013700002903039700002103068700002203089700002103111700001903132700002703151700002403178700002903202700003203231700002003263700001803283700003103301700002803332700001603360700002503376700003103401700003303432700002903465700002203494700002103516700002403537700001903561700002503580700001703605700001703622700001803639700002303657700002003680700001603700700002203716700002503738700001803763700002303781700002003804700002003824700002103844700003303865700001703898700002103915856012103936       2020                        eng d  a1468-624400aOptimised molecular genetic diagnostics of Fanconi anaemia by whole exome sequencing and functional studies.0 aOptimised molecular genetic diagnostics of Fanconi anaemia by wh  c2020 04  a258-2680 v573 a<p><b>PURPOSE: </b>Patients with Fanconi anaemia (FA), a rare DNA repair genetic disease, exhibit chromosome fragility, bone marrow failure, malformations and cancer susceptibility. FA molecular diagnosis is challenging since FA is caused by point mutations and large deletions in 22 genes following three heritability patterns. To optimise FA patients' characterisation, we developed a simplified but effective methodology based on whole exome sequencing (WES) and functional studies.</p><p><b>METHODS: </b>68 patients with FA were analysed by commercial WES services. Copy number variations were evaluated by sequencing data analysis with RStudio. To test  missense variants, wt FANCA cDNA was cloned and variants were introduced by site-directed mutagenesis. Vectors were then tested for their ability to complement DNA repair defects of a FANCA-KO human cell line generated by TALEN technologies.</p><p><b>RESULTS: </b>We identified 93.3% of mutated alleles including large deletions. We determined the pathogenicity of three FANCA missense variants and demonstrated that two  variants reported in mutations databases as 'affecting functions' are SNPs. Deep analysis of sequencing data revealed patients' true mutations, highlighting the importance of functional analysis. In one patient, no pathogenic variant could be identified in any of the 22 known FA genes, and in seven patients, only one deleterious variant could be identified (three patients each with FANCA and FANCD2 and one patient with FANCE mutations) CONCLUSION: WES and proper bioinformatics analysis are sufficient to effectively characterise patients with FA regardless of the rarity of their complementation group, type of mutations, mosaic condition and DNA source.</p>10aCell Line10aDNA Copy Number Variations10aDNA Repair10aDNA-Binding Proteins10aFanconi Anemia10aFanconi Anemia Complementation Group A Protein10aFemale10aGene Knockout Techniques10aGenetic Predisposition to Disease10aHumans10aMale10aMutation, Missense10aPolymorphism, Single Nucleotide10awhole exome sequencing1 aBogliolo, Massimo1 aPujol, Roser1 aAza-Carmona, Miriam1 aMuñoz-Subirana, Núria1 aRodriguez-Santiago, Benjamin1 aCasado, José, Antonio1 aRio, Paula1 aBauser, Christopher1 aReina-Castillón, Judith1 aLopez-Sanchez, Marcos1 aGonzalez-Quereda, Lidia1 aGallano, Pia1 aCatalá, Albert1 aRuiz-Llobet, Ana1 aBadell, Isabel1 aDiaz-Heredia, Cristina1 aHladun, Raquel1 aSenent, Leonort1 aArgiles, Bienvenida1 aBurgues, Juan, Miguel Ber1 aBañez, Fatima1 aArrizabalaga, Beatriz1 aAlmaraz, Ricardo, López1 aLopez, Monica1 aFiguera, Ángela1 aMolinés, Antonio1 ade Soto, Inmaculada, Pérez1 aHernando, Inés1 aMuñoz, Juan, Antonio1 aMarin, Maria, Del Rosari1 aBalmaña, Judith1 aStjepanovic, Neda1 aCarrasco, Estela1 aCuesta, Isabel1 aCosuelo, José, Miguel1 aRegueiro, Alexandra1 aJimenez, José, Moraleda1 aGalera-Miñarro, Ana, Maria1 aRosiñol, Laura1 aCarrió, Anna1 aBeléndez-Bieler, Cristina1 aSoto, Antonio, Escudero1 aCela, Elena1 ade la Mata, Gregorio1 aFernández-Delgado, Rafael1 aGarcia-Pardos, Maria, Carmen1 aSáez-Villaverde, Raquel1 aBarragaño, Marta1 aPortugal, Raquel1 aLendinez, Francisco1 aHernadez, Ines1 aVagace, José, Manue1 aTapia, Maria1 aNieto, José1 aGarcia, Marta1 aGonzalez, Macarena1 aVicho, Cristina1 aGalvez, Eva1 aValiente, Alberto1 aAntelo, Maria, Luisa1 aAncliff, Phil1 aGarcía, Francisco1 aDopazo, Joaquin1 aSevilla, Julian1 aPaprotka, Tobias1 aPérez-Jurado, Luis, Alberto1 aBueren, Juan1 aSurralles, Jordi  uhttp://clinbioinfosspa.es/content/optimised-molecular-genetic-diagnostics-fanconi-anaemia-whole-exome-sequencing-and04656nas a2200625   4500008004100000022001400041245010700055210006900162260001200231300001200243490000700255520277400262653000903036653001103045653002203056653001103078653001403089653000903103653001603112653002403128653001403152653002403166653003003190653001603220653004903236653002803285653001703313653001803330100002503348700001903373700001903392700001903411700001703430700001603447700002003463700002103483700002203504700003403526700002003560700002403580700002303604700001903627700002003646700002003666700002503686700002303711700002203734700002003756700002903776700003203805700002103837700002003858700002403878856012803902       2020                        eng d  a1474-548800aPazopanib for treatment of typical solitary fibrous tumours: a multicentre, single-arm, phase 2 trial.0 aPazopanib for treatment of typical solitary fibrous tumours a mu  c2020 03  a456-4660 v213 a<p><b>BACKGROUND: </b>Solitary fibrous tumour is an ultra-rare sarcoma, which encompasses different clinicopathological subgroups. The dedifferentiated subgroup shows an aggressive course with resistance to pazopanib, whereas in the malignant subgroup, pazopanib shows higher activity than in previous studies with chemotherapy. We designed a trial to test pazopanib activity in two different cohorts of solitary fibrous tumour: the malignant-dedifferentiated cohort, which was previously published, and the typical cohort, which is presented here.</p><p><b>METHODS: </b>In this single-arm, phase 2 trial, adult patients (aged ≥18 years) diagnosed with confirmed metastatic or unresectable typical solitary fibrous tumour of any location, who had progressed in the previous 6 months (by Choi criteria or Response Evaluation Criteria in Solid Tumors [RECIST]) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were enrolled at 11 tertiary hospitals in Italy, France, and Spain. Patients received pazopanib 800 mg once daily, taken orally, until progression, unacceptable toxicity, withdrawal of consent, non-compliance, or a delay in pazopanib administration of longer than 3 weeks. The primary endpoint was proportion of patients achieving an overall response measured by Choi criteria in patients who received at least 1 month of treatment with at least one radiological assessment. All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered in ClinicalTrials.gov, NCT02066285, and with the European Clinical Trials Database, EudraCT 2013-005456-15.</p><p><b>FINDINGS: </b>From June 26, 2014, to Dec 13, 2018, of 40 patients who were assessed, 34 patients were enrolled and 31 patients were included in the response analysis. Median follow-up was 18 months (IQR 14-34), and 18 (58%) of 31 patients had a partial response, 12 (39%) had stable disease, and one (3%) showed progressive disease according to Choi criteria and central review. The proportion of overall response based on Choi criteria was 58% (95% CI 34-69). There were no deaths caused by toxicity, and the most frequent adverse events were diarrhoea (18 [53%] of 34 patients), fatigue (17 [50%]), and hypertension (17 [50%]).</p><p><b>INTERPRETATION: </b>To our knowledge, this is the first prospective trial of pazopanib for advanced typical solitary fibrous tumour. The manageable toxicity and activity shown by pazopanib in this cohort suggest that this drug could be considered as first-line treatment for advanced typical solitary fibrous tumour.</p><p><b>FUNDING: </b>Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.</p>10aAged10aFemale10aFollow-Up Studies10aHumans10aIndazoles10aMale10aMiddle Aged10aNeoplasm Metastasis10aPrognosis10aProspective Studies10aProtein Kinase Inhibitors10aPyrimidines10aResponse Evaluation Criteria in Solid Tumors10aSolitary Fibrous Tumors10aSulfonamides10aSurvival Rate1 aMartin-Broto, Javier1 aCruz, Josefina1 aPenel, Nicolas1 aLe Cesne, Axel1 aHindi, Nadia1 aLuna, Pablo1 aMoura, David, S1 aBernabeu, Daniel1 ade Alava, Enrique1 aLopez-Guerrero, Jose, Antonio1 aDopazo, Joaquin1 aPeña-Chilet, Maria1 aGutierrez, Antonio1 aCollini, Paola1 aKaranian, Marie1 aRedondo, Andres1 aLopez-Pousa, Antonio1 aGrignani, Giovanni1 aDiaz-Martin, Juan1 aMarcilla, David1 aFernandez-Serra, Antonio1 aGonzalez-Aguilera, Cristina1 aCasali, Paolo, G1 aBlay, Jean-Yves1 aStacchiotti, Silvia  uhttp://clinbioinfosspa.es/content/pazopanib-treatment-typical-solitary-fibrous-tumours-multicentre-single-arm-phase-2-trial02753nas a2200373   4500008004100000022001400041245009300055210006900148260001500217300001400232490000700246520158800253653002801841653001101869653003501880653002401915653001801939653001301957653001701970653001801987653002202005100001702027700002102044700002102065700002002086700002902106700002002135700002202155700002002177700001902197700001702216700002302233856012302256       2020                        eng d  a1549-491800aPlatform to study intracellular polystyrene nanoplastic pollution and clinical outcomes.0 aPlatform to study intracellular polystyrene nanoplastic pollutio  c2020 10 01  a1321-13250 v383 a<p>Increased pollution by plastics has become a serious global environmental problem, but the concerns for human health have been raised after reported presence of microplastics (MPs) and nanoplastics (NPs) in food and beverages. Unfortunately, few studies have investigate the potentially harmful effects of MPs/NPs on early human development and human health. Therefore, we used a new platform to study possible effects of polystyrene NPs (PSNPs) on the transcription profile of preimplantation human embryos and human induced pluripotent stem cells (hiPSCs). Two pluripotency genes, LEFTY1 and LEFTY2, which encode secreted ligands of the transforming growth factor-beta, were downregulated, while CA4 and OCLM, which are related to eye development, were upregulated in both samples. The gene set enrichment analysis showed that the development of atrioventricular heart valves and the dysfunction of cellular components, including extracellular matrix, were significantly affected after exposure of hiPSCs to PSNPs. Finally, using the HiPathia method, which uncovers disease mechanisms and predicts clinical outcomes, we determined the APOC3 circuit, which is responsible for increased risk for ischemic cardiovascular disease. These results clearly demonstrate that better understanding of NPs bioactivities and its implications for human health is of extreme importance. Thus, the presented platform opens further aspects to study interactions between different environmental and intracellular pollutions with the aim to decipher the mechanism and origin of human diseases.</p>10aEnvironmental Pollution10aHumans10aInduced Pluripotent Stem Cells10aIntracellular Space10aNanoparticles10aPlastics10aPolystyrenes10aTranscriptome10aTreatment Outcome1 aBojic, Sanja1 aFalco, Matias, M1 aStojkovic, Petra1 aLjujic, Biljana1 aJankovic, Marina, Gazdic1 aArmstrong, Lyle1 aMarkovic, Nebojsa1 aDopazo, Joaquin1 aLako, Majlinda1 aBauer, Roman1 aStojkovic, Miodrag  uhttp://clinbioinfosspa.es/content/platform-study-intracellular-polystyrene-nanoplastic-pollution-and-clinical-outcomes02123nas a2200325   4500008004100000022001400041245008900055210006900144260001200213300001400225490000700239520106200246653001801308653003101326653004201357653001101399653003101410653001301441653003901454100002601493700002001519700002101539700002101560700002001581700002001601700002001621700001901641700002001660856011701680       2020                        eng d  a1098-100400aSMN1 copy-number and sequence variant analysis from next-generation sequencing data.0 aSMN1 copynumber and sequence variant analysis from nextgeneratio  c2020 12  a2073-20770 v413 a<p>Spinal muscular atrophy (SMA) is a severe neuromuscular autosomal recessive disorder affecting 1/10,000 live births. Most SMA patients present homozygous deletion of SMN1, while the vast majority of SMA carriers present only a single SMN1 copy. The sequence similarity between SMN1 and SMN2, and the complexity of the SMN locus makes the estimation of the SMN1 copy-number by next-generation sequencing (NGS) very difficult. Here, we present SMAca, the first python tool to detect SMA carriers and estimate the absolute SMN1 copy-number using NGS data. Moreover, SMAca takes advantage of the knowledge of certain variants specific to SMN1 duplication to also identify silent carriers. This tool has been validated with a cohort of 326 samples from the Navarra 1000 Genomes Project (NAGEN1000). SMAca was developed with a focus on execution speed and easy installation. This combination makes it especially suitable to be integrated into production NGS pipelines. Source code and documentation are available at https://www.github.com/babelomics/SMAca.</p>10aBase Sequence10aDNA Copy Number Variations10aHigh-Throughput Nucleotide Sequencing10aHumans10aReproducibility of Results10aSoftware10aSurvival of Motor Neuron 1 Protein1 aLópez-López, Daniel1 aLoucera, Carlos1 aCarmona, Rosario1 aAquino, Virginia1 aSalgado, Josefa1 aPasalodos, Sara1 aMiranda, María1 aAlonso, Ángel1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/smn1-copy-number-and-sequence-variant-analysis-next-generation-sequencing-data02695nas a2200325   4500008004100000022001400041245009200055210006900147260001200216300001400228490000700242520165100249653002201900653002601922653003301948653003001981653001102011653002102022653001202043653001902055100002002074700002902094700002102123700002102144700001802165700002002183700002502203700001902228856012202247       2020                        eng d  a2168-220800aTowards Improving Skin Cancer Diagnosis by Integrating Microarray and RNA-Seq Datasets.0 aTowards Improving Skin Cancer Diagnosis by Integrating Microarra  c2020 07  a2119-21300 v243 a<p>Many clinical studies have revealed the high biological similarities existing among different skin pathological states. These similarities create difficulties in the efficient diagnosis of skin cancer, and encourage to study and design new intelligent clinical decision support systems. In this sense, gene expression analysis can help find differentially expressed genes (DEGs) simultaneously discerning multiple skin pathological states in a single test. The integration of multiple heterogeneous transcriptomic datasets requires different pipeline stages to be properly designed: from suitable batch merging and efficient biomarker selection to automated classification assessment. This article presents a novel approach addressing all these technical issues, with the intention of providing new sights about skin cancer diagnosis. Although new future efforts will have to be made in the search for better biomarkers recognizing specific skin pathological states, our study found a panel of 8 highly relevant multiclass DEGs for discerning up to 10 skin pathological states: 2 healthy skin conditions a priori, 2 cataloged precancerous skin diseases and 6 cancerous skin states. Their power of diagnosis over new samples was widely tested by previously well-trained classification models. Robust performance metrics such as overall and mean multiclass F1-score outperformed recognition rates of 94% and 80%, respectively. Clinicians should give special attention to highlighted multiclass DEGs that have high gene expression changes present among them, and understand their biological relationship to different skin pathological states.</p>10aBiomarkers, Tumor10aComputational Biology10aDiagnosis, Computer-Assisted10aGene Expression Profiling10aHumans10aMachine Learning10aRNA-seq10aSkin Neoplasms1 aGalvez, Juan, M1 aCastillo-Secilla, Daniel1 aHerrera, Luis, J1 aValenzuela, Olga1 aCaba, Octavio1 aPrados, Jose, C1 aOrtuno, Francisco, M1 aRojas, Ignacio  uhttp://clinbioinfosspa.es/content/towards-improving-skin-cancer-diagnosis-integrating-microarray-and-rna-seq-datasets03110nas a2200493   4500008004100000022001400041245014400055210006900199260001500268490000700283520148700290653001201777653003601789653003001825653003101855653001801886653001101904653003601915653000901951653001501960653002401975653003401999653003302033653002402066653000902090653002502099653001502124653001702139653002302156653001802179653003402197653001802231100001802249700002902267700001702296700002402313700002102337700003102358700002002389700002102409700002602430700003402456856012602490       2020                        eng d  a2073-442500aTranscriptomic Analysis of a Diabetic Skin-Humanized Mouse Model Dissects Molecular Pathways Underlying the Delayed Wound Healing Response.0 aTranscriptomic Analysis of a Diabetic SkinHumanized Mouse Model   c2020 12 310 v123 a<p>Defective healing leading to cutaneous ulcer formation is one of the most feared complications of diabetes due to its consequences on patients' quality of life and on the healthcare system. A more in-depth analysis of the underlying molecular pathophysiology is required to develop effective healing-promoting therapies for those patients. Major architectural and functional differences with human epidermis limit extrapolation of results coming from rodents and other small mammal-healing models. Therefore, the search for reliable humanized models has become mandatory. Previously, we developed a diabetes-induced delayed humanized wound healing model that faithfully recapitulated the major histological features of such skin repair-deficient condition. Herein, we present the results of a transcriptomic and functional enrichment analysis followed by a mechanistic analysis performed in such humanized wound healing model. The deregulation of genes implicated in functions such as angiogenesis, apoptosis, and inflammatory signaling processes were evidenced, confirming published data in diabetic patients that in fact might also underlie some of the histological features previously reported in the delayed skin-humanized healing model. Altogether, these molecular findings support the utility of such preclinical model as a valuable tool to gain insight into the molecular basis of the delayed diabetic healing with potential impact in the translational medicine field.</p>10aAnimals10aDiabetes Mellitus, Experimental10aGene Expression Profiling10aGene Expression Regulation10aGene ontology10aHumans10aMetabolic Networks and Pathways10aMice10aMice, Nude10aMicroarray Analysis10aMolecular Sequence Annotation10aPrincipal Component Analysis10aSignal Transduction10aSkin10aSkin Transplantation10aSkin Ulcer10aStreptozocin10aTissue Engineering10aTranscriptome10aTransplantation, Heterologous10aWound Healing1 aLeón, Carlos1 aGarcia-Garcia, Francisco1 aLlames, Sara1 aGarcía-Pérez, Eva1 aCarretero, Marta1 aArriba, María, Del Carmen1 aDopazo, Joaquin1 aDel Rio, Marcela1 aEscamez, Maria, José1 aMartínez-Santamaría, Lucía  uhttp://clinbioinfosspa.es/content/transcriptomic-analysis-diabetic-skin-humanized-mouse-model-dissects-molecular-pathways03264nas a2200685   4500008004100000022001400041245011800055210006900173260001500242300000900257490000700266520115400273653001901427653005101446653001701497653002201514653002101536653002601557653002201583653002001605653003001625653001901655653001301674653001101687653003101698653001301729653001401742653002101756653003501777653004101812653002201853100002301875700001701898700001901915700001801934700002301952700001901975700001501994700001702009700001602026700002002042700001602062700002402078700001902102700001802121700002402139700001802163700002502181700001702206700001902223700002302242700002702265700002002292700002502312700002002337700002102357700002602378710005702404856011702461       2019                        eng d  a2041-172300aCommunity assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen.0 aCommunity assessment to advance computational prediction of canc  c2019 06 17  a26740 v103 a<p>The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca's large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.</p>10aADAM17 Protein10aAntineoplastic Combined Chemotherapy Protocols10aBenchmarking10aBiomarkers, Tumor10aCell Line, Tumor10aComputational Biology10aDatasets as Topic10aDrug Antagonism10aDrug Resistance, Neoplasm10aDrug Synergism10aGenomics10aHumans10aMolecular Targeted Therapy10amutation10aNeoplasms10apharmacogenetics10aPhosphatidylinositol 3-Kinases10aPhosphoinositide-3 Kinase Inhibitors10aTreatment Outcome1 aMenden, Michael, P1 aWang, Dennis1 aMason, Mike, J1 aSzalai, Bence1 aBulusu, Krishna, C1 aGuan, Yuanfang1 aYu, Thomas1 aKang, Jaewoo1 aJeon, Minji1 aWolfinger, Russ1 aNguyen, Tin1 aZaslavskiy, Mikhail1 aJang, In, Sock1 aGhazoui, Zara1 aAhsen, Mehmet, Eren1 aVogel, Robert1 aNeto, Elias, Chaibub1 aNorman, Thea1 aK Y Tang, Eric1 aGarnett, Mathew, J1 aDi Veroli, Giovanni, Y1 aFawell, Stephen1 aStolovitzky, Gustavo1 aGuinney, Justin1 aDry, Jonathan, R1 aSaez-Rodriguez, Julio1 aAstraZeneca-Sanger Drug Combination DREAM Consortium  uhttp://clinbioinfosspa.es/content/community-assessment-advance-computational-prediction-cancer-drug-combinations01814nas a2200265   4500008004100000022001400041245007700055210006900132260001600201300001400217490000700231520098400238653001501222653001101237653002301248653002401271653002001295653001801315100001901333700002201352700001801374700003101392700002001423856010501443       2019                        eng d  a1477-405400aA comparison of mechanistic signaling pathway activity analysis methods.0 acomparison of mechanistic signaling pathway activity analysis me  c2019 Sep 27  a1655-16680 v203 a<p>Understanding the aspects of cell functionality that account for disease mechanisms or drug modes of action is a main challenge for precision medicine. Classical gene-based approaches ignore the modular nature of most human traits, whereas conventional pathway enrichment approaches produce only illustrative results of limited practical utility. Recently, a family of new methods has emerged that change the focus from the whole pathways to the definition of elementary subpathways within them that have any mechanistic significance and to the study of their activities. Thus, mechanistic pathway activity (MPA) methods constitute a new paradigm that allows recoding poorly informative genomic measurements into cell activity quantitative values and relate them to phenotypes. Here we provide a review on the MPA methods available and explain their contribution to systems medicine approaches for addressing challenges in the diagnostic and treatment of complex diseases.</p>10aAlgorithms10aHumans10aPostmortem Changes10aSignal Transduction10aSystems biology10aTranscriptome1 aAmadoz, Alicia1 aHidalgo, Marta, R1 aCubuk, Cankut1 aCarbonell-Caballero, José1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/comparison-mechanistic-signaling-pathway-activity-analysis-methods02834nas a2200397   4500008004100000022001400041245011600055210006900171260000900240300000600249490000600255520157600261653002601837653002401863653001901887653002901906653001101935653001301946653003601959653002301995653001402018653001402032653001302046653001802059100001802077700002202095700001902117700001602136700002402152700002202176700002102198700002002219700003102239700002002270856014602290       2019                        eng d  a2056-718900aDifferential metabolic activity and discovery of therapeutic targets using summarized metabolic pathway models.0 aDifferential metabolic activity and discovery of therapeutic tar  c2019  a70 v53 a<p>In spite of the increasing availability of genomic and transcriptomic data, there is still a gap between the detection of perturbations in gene expression and the understanding of their contribution to the molecular mechanisms that ultimately account for the phenotype studied. Alterations in the metabolism are behind the initiation and progression of many diseases, including cancer. The wealth of available knowledge on metabolic processes can therefore be used to derive mechanistic models that link gene expression perturbations to changes in metabolic activity that provide relevant clues on molecular mechanisms of disease and drug modes of action (MoA). In particular, pathway modules, which recapitulate the main aspects of metabolism, are especially suitable for this type of modeling. We present Metabolizer, a web-based application that offers an intuitive, easy-to-use interactive interface to analyze differences in pathway metabolic module activities that can also be used for class prediction and in silico prediction of knock-out (KO) effects. Moreover, Metabolizer can automatically predict the optimal KO intervention for restoring a diseased phenotype. We provide different types of validations of some of the predictions made by Metabolizer. Metabolizer is a web tool that allows understanding molecular mechanisms of disease or the MoA of drugs within the context of the metabolism by using gene expression measurements. In addition, this tool automatically suggests potential therapeutic targets for individualized therapeutic interventions.</p>10aComputational Biology10aComputer Simulation10aDrug discovery10aGene Regulatory Networks10aHumans10aInternet10aMetabolic Networks and Pathways10aModels, Biological10aNeoplasms10aPhenotype10aSoftware10aTranscriptome1 aCubuk, Cankut1 aHidalgo, Marta, R1 aAmadoz, Alicia1 aRian, Kinza1 aSalavert, Francisco1 aPujana, Miguel, A1 aMateo, Francesca1 aHerranz, Carmen1 aCarbonell-Caballero, José1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/differential-metabolic-activity-and-discovery-therapeutic-targets-using-summarized-metabolic-pathway-models01957nas a2200277   4500008004100000022001400041245011500055210006900170260001600239300000800255490000700263520105900270653002301329653001901352653001301371653001101384653002101395653001401416653001301430653002401443100002701467700002401494700002001518700002001538856012101558       2019                        eng d  a1471-210500aExploring the druggable space around the Fanconi anemia pathway using machine learning and mechanistic models.0 aExploring the druggable space around the Fanconi anemia pathway   c2019 Jul 02  a3700 v203 a<p><b>BACKGROUND: </b>In spite of the abundance of genomic data, predictive models that describe phenotypes as a function of gene expression or mutations are difficult to obtain because they are affected by the curse of dimensionality, given the disbalance between samples and candidate genes. And this is especially dramatic in scenarios in which the availability of samples is difficult, such as the case of rare diseases.</p><p><b>RESULTS: </b>The application of multi-output regression machine learning methodologies to predict the potential effect of external proteins over the signaling circuits that trigger Fanconi anemia related cell functionalities, inferred with a mechanistic model, allowed us to detect over 20 potential therapeutic targets.</p><p><b>CONCLUSIONS: </b>The use of artificial intelligence methods for the prediction of potentially causal relationships between proteins of interest and cell activities related with disease-related phenotypes opens promising avenues for the systematic search of new targets in rare diseases.</p>10aDatabases, Factual10aFanconi Anemia10aGenomics10aHumans10aMachine Learning10aPhenotype10aProteins10aSignal Transduction1 aEsteban-Medina, Marina1 aPeña-Chilet, Maria1 aLoucera, Carlos1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/exploring-druggable-space-around-fanconi-anemia-pathway-using-machine-learning-and05141nas a2200745   4500008004100000022001400041245013000055210006900185260001200254300001200266490000800278520304400286653001503330653001003345653001103355653001203366653002503378653002003403653001003423653002103433653002603454653003803480653002503518653003403543653001103577653001603588653001303604653003103617653002303648653001103671653001103682653002003693653000903713653001603722653001303738653002503751653003103776653002503807653001203832653000903844653002603853653001603879100002203895700001303917700001303930700002303943700001503966700001903981700002404000700001604024700001604040700002904056700001404085700001504099700002704114700002404141700001404165700001204179700001604191700001504207700001504222700001404237700001504251856012904266       2019                        eng d  a1365-213300aFibroblast activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer-prone genodermatoses.0 aFibroblast activation and abnormal extracellular matrix remodell  c2019 09  a512-5220 v1813 a<p><b>BACKGROUND: </b>Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three cancer-prone genodermatoses whose causal genetic mutations cannot fully explain, on their own, the array of associated phenotypic manifestations. Recent evidence highlights the role of the stromal microenvironment in the pathology of these disorders.</p><p><b>OBJECTIVES: </b>To investigate, by means of comparative gene expression analysis, the role played by dermal fibroblasts in the pathogenesis of RDEB, KS and XPC.</p><p><b>METHODS: </b>We conducted RNA-Seq analysis, which included a thorough examination of the differentially expressed genes, a functional enrichment analysis and a description of affected signalling circuits. Transcriptomic data were validated at the protein level in cell cultures, serum samples and skin biopsies.</p><p><b>RESULTS: </b>Interdisease comparisons against control fibroblasts revealed a unifying signature of 186 differentially expressed genes and four signalling pathways in the three genodermatoses. Remarkably, some of the uncovered expression changes suggest a synthetic fibroblast phenotype characterized by the aberrant expression of extracellular matrix (ECM) proteins. Western blot and immunofluorescence in situ analyses validated the RNA-Seq data. In addition, enzyme-linked immunosorbent assay revealed increased circulating levels of periostin in patients with RDEB.</p><p><b>CONCLUSIONS: </b>Our results suggest that the different causal genetic defects converge into common changes in gene expression, possibly due to injury-sensitive events. These, in turn, trigger a cascade of reactions involving abnormal ECM deposition and underexpression of antioxidant enzymes. The elucidated expression signature provides new potential biomarkers and common therapeutic targets in RDEB, XPC and KS. What's already known about this topic? Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three genodermatoses with high predisposition to cancer development. Although their causal genetic mutations mainly affect epithelia, the dermal microenvironment likely contributes to the physiopathology of these disorders. What does this study add? We disclose a large overlapping transcription profile between XPC, KS and RDEB fibroblasts that points towards an activated phenotype with high matrix-synthetic capacity. This common signature seems to be independent of the primary causal deficiency, but reflects an underlying derangement of the extracellular matrix via transforming growth factor-β signalling activation and oxidative state imbalance. What is the translational message? This study broadens the current knowledge about the pathology of these diseases and highlights new targets and biomarkers for effective therapeutic intervention. It is suggested that high levels of circulating periostin could represent a potential biomarker in RDEB.</p>10aAdolescent10aAdult10aBiopsy10aBlister10aCase-Control Studies10aCells, Cultured10aChild10aChild, Preschool10aEpidermolysis Bullosa10aEpidermolysis Bullosa Dystrophica10aExtracellular Matrix10aExtracellular Matrix Proteins10aFemale10aFibroblasts10aFibrosis10aGene Expression Regulation10aHealthy Volunteers10aHumans10aInfant10aInfant, Newborn10aMale10aMiddle Aged10amutation10aPeriodontal Diseases10aPhotosensitivity Disorders10aPrimary Cell Culture10aRNA-seq10aSkin10aXeroderma Pigmentosum10aYoung Adult1 aChacón-Solano, E1 aLeón, C1 aDíaz, F1 aGarcía-García, F1 aGarcía, M1 aEscámez, M, J1 aGuerrero-Aspizua, S1 aConti, C, J1 aMencía, Á1 aMartínez-Santamaría, L1 aLlames, S1 aPévida, M1 aCarbonell-Caballero, J1 aPuig-Butillé, J, A1 aMaseda, R1 aPuig, S1 ade Lucas, R1 aBaselga, E1 aLarcher, F1 aDopazo, J1 aDel Rio, M  uhttp://clinbioinfosspa.es/content/fibroblast-activation-and-abnormal-extracellular-matrix-remodelling-common-hallmarks-three05219nas a2200661   4500008004100000022001400041245013800055210006900193260001300262300001200275490000700287520316900294653001003463653000903473653002803482653002603510653001103536653001103547653001403558653000903572653001603581653002603597653001603623653004903639653002603688653002803714653001703742653002203759100002503781700002403806700002503830700002003855700002103875700002203896700002103918700002203939700002303961700002003984700002404004700002204028700002204050700001804072700001904090700003004109700002904139700002304168700001804191700002904209700002404238700001704262700001504279700002004294700002704314700001804341700002004359700001904379856015904398       2019                        eng d  a1474-548800aPazopanib for treatment of advanced malignant and dedifferentiated solitary fibrous tumour: a multicentre, single-arm, phase 2 trial.0 aPazopanib for treatment of advanced malignant and dedifferentiat  c2019 Jan  a134-1440 v203 a<p><b>BACKGROUND: </b>A solitary fibrous tumour is a rare soft-tissue tumour with three clinicopathological variants: typical, malignant, and dedifferentiated. Preclinical experiments and retrospective studies have shown different sensitivities of solitary fibrous tumour to chemotherapy and antiangiogenics. We therefore designed a trial to assess the activity of pazopanib in a cohort of patients with malignant or dedifferentiated solitary fibrous tumour. The clinical and translational results are presented here.</p><p><b>METHODS: </b>In this single-arm, phase 2 trial, adult patients (aged ≥ 18 years) with histologically confirmed metastatic or unresectable malignant or dedifferentiated solitary fibrous tumour at any location, who had progressed (by RECIST and Choi criteria) in the previous 6 months and had an ECOG performance status of 0-2, were enrolled at 16 third-level hospitals with expertise in sarcoma care in Spain, Italy, and France. Patients received pazopanib 800 mg once daily, taken orally without food, at least 1 h before or 2 h after a meal, until progression or intolerance. The primary endpoint of the study was overall response measured by Choi criteria in the subset of the intention-to-treat population (patients who received at least 1 month of treatment with at least one radiological assessment). All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02066285, and with the European Clinical Trials Database, EudraCT number 2013-005456-15.</p><p><b>FINDINGS: </b>From June 26, 2014, to Nov 24, 2016, of 40 patients assessed, 36 were enrolled (34 with malignant solitary fibrous tumour and two with dedifferentiated solitary fibrous tumour). Median follow-up was 27 months (IQR 16-31). Based on central radiology review, 18 (51%) of 35 evaluable patients had partial responses, nine (26%) had stable disease, and eight (23%) had progressive disease according to Choi criteria. Further enrolment of patients with dedifferentiated solitary fibrous tumour was stopped after detection of early and fast progressions in a planned interim analysis. 51% (95% CI 34-69) of 35 patients achieved an overall response according to Choi criteria. Ten (29%) of 35 patients died. There were no deaths related to adverse events and the most frequent grade 3 or higher adverse events were hypertension (11 [31%] of 36 patients), neutropenia (four [11%]), increased concentrations of alanine aminotransferase (four [11%]), and increased concentrations of bilirubin (three [8%]).</p><p><b>INTERPRETATION: </b>To our knowledge, this is the first trial of pazopanib for treatment of malignant solitary fibrous tumour showing activity in this patient group. The manageable toxicity profile and the activity shown by pazopanib suggests that this drug could be an option for systemic treatment of advanced malignant solitary fibrous tumour, and provides a benchmark for future trials.</p><p><b>FUNDING: </b>Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.</p>10aAdult10aAged10aAngiogenesis Inhibitors10aAntineoplastic Agents10aFemale10aHumans10aIndazoles10aMale10aMiddle Aged10aMultivariate Analysis10aPyrimidines10aResponse Evaluation Criteria in Solid Tumors10aSoft Tissue Neoplasms10aSolitary Fibrous Tumors10aSulfonamides10aSurvival Analysis1 aMartin-Broto, Javier1 aStacchiotti, Silvia1 aLopez-Pousa, Antonio1 aRedondo, Andres1 aBernabeu, Daniel1 ade Alava, Enrique1 aCasali, Paolo, G1 aItaliano, Antoine1 aGutierrez, Antonio1 aMoura, David, S1 aPeña-Chilet, Maria1 aDiaz-Martin, Juan1 aBiscuola, Michele1 aTaron, Miguel1 aCollini, Paola1 aRanchere-Vince, Dominique1 aDel Muro, Xavier, Garcia1 aGrignani, Giovanni1 aDumont, Sarah1 aMartinez-Trufero, Javier1 aPalmerini, Emanuela1 aHindi, Nadia1 aSebio, Ana1 aDopazo, Joaquin1 aTos, Angelo, Paolo Dei1 aLeCesne, Axel1 aBlay, Jean-Yves1 aCruz, Josefina  uhttp://clinbioinfosspa.es/content/pazopanib-treatment-advanced-malignant-and-dedifferentiated-solitary-fibrous-tumour-multicentre-single-arm-phase-2-trial02190nas a2200241   4500008004100000022001400041245006800055210006700123260001600190300001200206490000700218520142700225653001901652653002601671653001101697653002301708100002701731700002001758700002201778700002201800700002501822856010101847       2019                        eng d  a1477-405400aPrecision medicine needs pioneering clinical bioinformaticians.0 aPrecision medicine needs pioneering clinical bioinformaticians  c2019 May 21  a752-7660 v203 a<p>Success in precision medicine depends on accessing high-quality genetic and molecular data from large, well-annotated patient cohorts that couple biological samples to comprehensive clinical data, which in conjunction can lead to effective therapies. From such a scenario emerges the need for a new professional profile, an expert bioinformatician with training in clinical areas who can make sense of multi-omics data to improve therapeutic interventions in patients, and the design of optimized basket trials. In this review, we first describe the main policies and international initiatives that focus on precision medicine. Secondly, we review the currently ongoing clinical trials in precision medicine, introducing the concept of 'precision bioinformatics', and we describe current pioneering bioinformatics efforts aimed at implementing tools and computational infrastructures for precision medicine in health institutions around the world. Thirdly, we discuss the challenges related to the clinical training of bioinformaticians, and the urgent need for computational specialists capable of assimilating medical terminologies and protocols to address real clinical questions. We also propose some skills required to carry out common tasks in clinical bioinformatics and some tips for emergent groups. Finally, we explore the future perspectives and the challenges faced by precision medicine bioinformatics.</p>10aCohort Studies10aComputational Biology10aHumans10aPrecision Medicine1 aGómez-López, Gonzalo1 aDopazo, Joaquin1 aCigudosa, Juan, C1 aValencia, Alfonso1 aAl-Shahrour, Fátima  uhttp://clinbioinfosspa.es/content/precision-medicine-needs-pioneering-clinical-bioinformaticians02573nas a2200529   4500008004100000022001400041245008700055210006900142260001600211300000800227490000600235520103000241653001001271653001801281653001001299653001101309653002001320653001101340653002301351653002301374653001901397653002501416653001801441100002301459700002701482700002101509700002501530700001601555700001901571700001701590700002201607700002401629700003101653700002101684700002401705700001901729700002401748700001801772700001801790700002101808700002001829700002001849700002101869700002301890700002001913856011001933       2018                        eng d  a2041-172300aThe effects of death and post-mortem cold ischemia on human tissue transcriptomes.0 aeffects of death and postmortem cold ischemia on human tissue tr  c2018 Feb 13  a4900 v93 a<p>Post-mortem tissues samples are a key resource for investigating patterns of gene expression. However, the processes triggered by death and the post-mortem interval (PMI) can significantly alter physiologically normal RNA levels. We investigate the impact of PMI on gene expression using data from multiple tissues of post-mortem donors obtained from the GTEx project. We find that many genes change expression over relatively short PMIs in a tissue-specific manner, but this potentially confounding effect in a biological analysis can be minimized by taking into account appropriate covariates. By comparing ante- and post-mortem blood samples, we identify the cascade of transcriptional events triggered by death of the organism. These events do not appear to simply reflect stochastic variation resulting from mRNA degradation, but active and ongoing regulation of transcription. Finally, we develop a model to predict the time since death from the analysis of the transcriptome of a few readily accessible tissues.</p>10aBlood10aCold Ischemia10aDeath10aFemale10agene expression10aHumans10aModels, Biological10aPostmortem Changes10aRNA, Messenger10aStochastic Processes10aTranscriptome1 aFerreira, Pedro, G1 aMuñoz-Aguirre, Manuel1 aReverter, Ferran1 aGodinho, Caio, P Sá1 aSousa, Abel1 aAmadoz, Alicia1 aSodaei, Reza1 aHidalgo, Marta, R1 aPervouchine, Dmitri1 aCarbonell-Caballero, José1 aNurtdinov, Ramil1 aBreschi, Alessandra1 aAmador, Raziel1 aOliveira, Patrícia1 aCubuk, Cankut1 aCurado, João1 aAguet, François1 aOliveira, Carla1 aDopazo, Joaquin1 aSammeth, Michael1 aArdlie, Kristin, G1 aGuigó, Roderic  uhttp://clinbioinfosspa.es/content/effects-death-and-post-mortem-cold-ischemia-human-tissue-transcriptomes02711nas a2200373   4500008004100000022001400041245014700055210006900202260001600271300000900287490000600296520150800302653002801810653002901838653001901867653002001886653001101906653001301917653001901930653002601949100001401975700001301989700001802002700001402020700002602034700001502060700002502075700002702100700001202127700001502139700001102154700001302165856015902178       2018                        eng d  a2045-232200aEvolution of the Quorum network and the mobilome (plasmids and bacteriophages) in clinical strains of Acinetobacter baumannii during a decade.0 aEvolution of the Quorum network and the mobilome plasmids and ba  c2018 Feb 06  a25230 v83 a<p>In this study, we compared eighteen clinical strains of A. baumannii belonging to the ST-2 clone and isolated from patients in the same intensive care unit (ICU) in 2000 (9 strains referred to collectively as Ab_GEIH-2000) and 2010 (9 strains referred to collectively as Ab_GEIH-2010), during the GEIH-REIPI project (Umbrella BioProject PRJNA422585). We observed two main molecular differences between the Ab_GEIH-2010 and the Ab_GEIH-2000 collections, acquired over the course of the decade long sampling interval and involving the mobilome: i) a plasmid harbouring genes for bla ß-lactamase and abKA/abkB proteins of a toxin-antitoxin system; and ii) two temperate bacteriophages, Ab105-1ϕ (63 proteins) and Ab105-2ϕ (93 proteins), containing important viral defence proteins. Moreover, all Ab_GEIH-2010 strains contained a Quorum functional network of Quorum Sensing (QS) and Quorum Quenching (QQ) mechanisms, including a new QQ enzyme, AidA, which acts as a bacterial defence mechanism against the exogenous 3-oxo-C12-HSL. Interestingly, the infective capacity of the bacteriophages isolated in this study (Ab105-1ϕ and Ab105-2ϕ) was higher in the Ab_GEIH-2010 strains (carrying a functional Quorum network) than in the Ab_GEIH-2000 strains (carrying a deficient Quorum network), in which the bacteriophages showed little or no infectivity. This is the first study about the evolution of the Quorum network and the mobilome in clinical strains of Acinetobacter baumannii during a decade.</p>10aAcinetobacter baumannii10aAcinetobacter Infections10aBacteriophages10aCross Infection10aHumans10aPlasmids10aQuorum Sensing10aRetrospective Studies1 aLópez, M1 aRueda, A1 aFlorido, J, P1 aBlasco, L1 aFernández-García, L1 aTrastoy, R1 aFernández-Cuenca, F1 aMartínez-Martínez, L1 aVila, J1 aPascual, A1 aBou, G1 aTomas, M  uhttp://clinbioinfosspa.es/content/evolution-quorum-network-and-mobilome-plasmids-and-bacteriophages-clinical-strains-acinetobacter-baumannii-during-decade02783nas a2200349   4500008004100000022001400041245008700055210006900142260001300211490000600224520171300230653001201943653003001955653001101985653002201996653001302018653001102031653000902042653001002051653002702061100003302088700002902121700002002150700003002170700002102200700001902221700002002240700001902260700001902279700002202298856011302320       2018                        eng d  a2057-585800aThe first complete genomic structure of Butyrivibrio fibrisolvens and its chromid.0 afirst complete genomic structure of Butyrivibrio fibrisolvens an  c2018 Oct0 v43 a<p>Butyrivibrio fibrisolvens forms part of the gastrointestinal microbiome of ruminants and other mammals, including humans. Indeed, it is one of the most common bacteria found in the rumen and plays an important role in ruminal fermentation of polysaccharides, yet, to date, there is no closed reference genome published for this species in any ruminant animal. We successfully assembled the nearly complete genome sequence of B. fibrisolvens strain INBov1 isolated from cow rumen using Illumina paired-end reads, 454 Roche single-end and mate pair sequencing technology. Additionally, we constructed an optical restriction map of this strain to aid in scaffold ordering and positioning, and completed the first genomic structure of this species. Moreover, we identified and assembled the first chromid of this species (pINBov266). The INBov1 genome encodes a large set of genes involved in the cellulolytic process but lacks key genes. This seems to indicate that B. fibrisolvens plays an important role in ruminal cellulolytic processes, but does not have autonomous cellulolytic capacity. When searching for genes involved in the biohydrogenation of unsaturated fatty acids, no linoleate isomerase gene was found in this strain. INBov1 does encode oleate hydratase genes known to participate in the hydrogenation of oleic acids. Furthermore, INBov1 contains an enolase gene, which has been recently determined to participate in the synthesis of conjugated linoleic acids. This work confirms the presence of a novel chromid in B. fibrisolvens and provides a new potential reference genome sequence for this species, providing new insight into its role in biohydrogenation and carbohydrate degradation.</p>10aAnimals10aButyrivibrio fibrisolvens10aCattle10aGenome, Bacterial10aGenomics10aHumans10aMilk10aRumen10aSequence Analysis, DNA1 aHernáez, Javier, Rodríguez1 aCucchi, Maria, Esperanza1 aCravero, Silvio1 aMartinez, Maria, Carolina1 aGonzalez, Sergio1 aPuebla, Andrea1 aDopazo, Joaquin1 aFarber, Marisa1 aPaniego, Norma1 aRivarola, Máximo  uhttp://clinbioinfosspa.es/content/first-complete-genomic-structure-butyrivibrio-fibrisolvens-and-its-chromid02946nas a2200445   4500008004100000022001400041245009500055210006900150260001600219300001400235490000700249520156700256653002101823653002101844653002401865653003001889653004301919653002901962653001101991653002602002653001502028653001302043653001402056653001402070653001402084653001402098653002702112653002702139653001802166653002202184100001802206700002202224700001902246700002202265700002102287700002002308700003102328700002002359856012102379       2018                        eng d  a1538-744500aGene Expression Integration into Pathway Modules Reveals a Pan-Cancer Metabolic Landscape.0 aGene Expression Integration into Pathway Modules Reveals a PanCa  c2018 Nov 01  a6059-60720 v783 a<p>Metabolic reprogramming plays an important role in cancer development and progression and is a well-established hallmark of cancer. Despite its inherent complexity, cellular metabolism can be decomposed into functional modules that represent fundamental metabolic processes. Here, we performed a pan-cancer study involving 9,428 samples from 25 cancer types to reveal metabolic modules whose individual or coordinated activity predict cancer type and outcome, in turn highlighting novel therapeutic opportunities. Integration of gene expression levels into metabolic modules suggests that the activity of specific modules differs between cancers and the corresponding tissues of origin. Some modules may cooperate, as indicated by the positive correlation of their activity across a range of tumors. The activity of many metabolic modules was significantly associated with prognosis at a stronger magnitude than any of their constituent genes. Thus, modules may be classified as tumor suppressors and oncomodules according to their potential impact on cancer progression. Using this modeling framework, we also propose novel potential therapeutic targets that constitute alternative ways of treating cancer by inhibiting their reprogrammed metabolism. Collectively, this study provides an extensive resource of predicted cancer metabolic profiles and dependencies. Combining gene expression with metabolic modules identifies molecular mechanisms of cancer undetected on an individual gene level and allows discovery of new potential therapeutic targets. .</p>10aCell Line, Tumor10aCluster Analysis10aDisease Progression10aGene Expression Profiling10aGene Expression Regulation, Neoplastic10aGene Regulatory Networks10aHumans10aKaplan-Meier Estimate10aMetabolome10amutation10aNeoplasms10aOncogenes10aPhenotype10aPrognosis10aRNA, Small Interfering10aSequence Analysis, RNA10aTranscriptome10aTreatment Outcome1 aCubuk, Cankut1 aHidalgo, Marta, R1 aAmadoz, Alicia1 aPujana, Miguel, A1 aMateo, Francesca1 aHerranz, Carmen1 aCarbonell-Caballero, José1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/gene-expression-integration-pathway-modules-reveals-pan-cancer-metabolic-landscape03413nas a2200793   4500008004100000022001400041245009300055210006900148260001600217300000900233490000600242520096600248653001201214653001401226653002301240653001801263653003601281653003001317653001101347653003101358653001101389653002401400653002101424653001201445653002801457653002501485653004101510653001601551653000901567653000901576653002301585653001501608653003901623653001701662653003001679653003401709100002801743700002201771700003201793700002901825700002601854700002601880700003101906700003301937700002201970700003101992700001902023700002002042700002002062700002202082700002002104700002302124700001602147700002302163700002302186700002302209700001902232700002502251700002902276700002102305700002502326700003202351700001602383700001802399700003802417700001702455700002402472856012302496       2018                        eng d  a2041-172300aLRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus.0 aLRH1 agonism favours an immuneislet dialogue which protects agai  c2018 Apr 16  a14880 v93 a<p>Type 1 diabetes mellitus (T1DM) is due to the selective destruction of islet beta cells by immune cells. Current therapies focused on repressing the immune attack or stimulating beta cell regeneration still have limited clinical efficacy. Therefore, it is timely to identify innovative targets to dampen the immune process, while promoting beta cell survival and function. Liver receptor homologue-1 (LRH-1) is a nuclear receptor that represses inflammation in digestive organs, and protects pancreatic islets against apoptosis. Here, we show that BL001, a small LRH-1 agonist, impedes hyperglycemia progression and the immune-dependent inflammation of pancreas in murine models of T1DM, and beta cell apoptosis in islets of type 2 diabetic patients, while increasing beta cell mass and insulin secretion. Thus, we suggest that LRH-1 agonism favors a dialogue between immune and islet cells, which could be druggable to protect against diabetes mellitus.</p>10aAnimals10aApoptosis10aCell Communication10aCell Survival10aDiabetes Mellitus, Experimental10aDiabetes Mellitus, Type 210aFemale10aGene Expression Regulation10aHumans10aHypoglycemic Agents10aImmunity, Innate10ainsulin10aInsulin-Secreting Cells10aIslets of Langerhans10aIslets of Langerhans Transplantation10aMacrophages10aMale10aMice10aMice, Inbred C57BL10aPhenalenes10aReceptors, Cytoplasmic and Nuclear10aStreptozocin10aT-Lymphocytes, Regulatory10aTransplantation, Heterologous1 aCobo-Vuilleumier, Nadia1 aLorenzo, Petra, I1 aRodríguez, Noelia, García1 aGómez, Irene, de Gracia1 aFuente-Martin, Esther1 aLópez-Noriega, Livia1 aMellado-Gil, José, Manuel1 aRomero-Zerbo, Silvana-Yanina1 aBaquié, Mathurin1 aLachaud, Christian, Claude1 aStifter, Katja1 aPerdomo, German1 aBugliani, Marco1 aDe Tata, Vincenzo1 aBosco, Domenico1 aParnaud, Geraldine1 aPozo, David1 aHmadcha, Abdelkrim1 aFlorido, Javier, P1 aToscano, Miguel, G1 ade Haan, Peter1 aSchoonjans, Kristina1 aPalazón, Luis, Sánchez1 aMarchetti, Piero1 aSchirmbeck, Reinhold1 aMartín-Montalvo, Alejandro1 aMeda, Paolo1 aSoria, Bernat1 aBermúdez-Silva, Francisco-Javier1 aSt-Onge, Luc1 aGauthier, Benoit, R  uhttp://clinbioinfosspa.es/content/lrh-1-agonism-favours-immune-islet-dialogue-which-protects-against-diabetes-mellitus02251nas a2200277   4500008004100000022001400041245011400055210006900169260001600238300000700254490000700261520126600268653002601534653004301560653001101603653004201614653002401656653001801680653002401698100002201722700001901744700001801763700003101781700002001812856014101832       2018                        eng d  a1745-615000aModels of cell signaling uncover molecular mechanisms of high-risk neuroblastoma and predict disease outcome.0 aModels of cell signaling uncover molecular mechanisms of highris  c2018 Aug 22  a160 v133 a<p><b>BACKGROUND: </b>Despite the progress in neuroblastoma therapies the mortality of high-risk patients is still high (40-50%) and the molecular basis of the disease remains poorly known. Recently, a mathematical model was used to demonstrate that the network regulating stress signaling by the c-Jun N-terminal kinase pathway played a crucial role in survival of patients with neuroblastoma irrespective of their MYCN amplification status. This demonstrates the enormous potential of computational models of biological modules for the discovery of underlying molecular mechanisms of diseases.</p><p><b>RESULTS: </b>Since signaling is known to be highly relevant in cancer, we have used a computational model of the whole cell signaling network to understand the molecular determinants of bad prognostic in neuroblastoma. Our model produced a comprehensive view of the molecular mechanisms of neuroblastoma tumorigenesis and progression.</p><p><b>CONCLUSION: </b>We have also shown how the activity of signaling circuits can be considered a reliable model-based prognostic biomarker.</p><p><b>REVIEWERS: </b>This article was reviewed by Tim Beissbarth, Wenzhong Xiao and Joanna Polanska. For the full reviews, please go to the Reviewers' comments section.</p>10aComputational Biology10aGene Expression Regulation, Neoplastic10aHumans10aJNK Mitogen-Activated Protein Kinases10aModels, Theoretical10aNeuroblastoma10aSignal Transduction1 aHidalgo, Marta, R1 aAmadoz, Alicia1 aCubuk, Cankut1 aCarbonell-Caballero, José1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/models-cell-signaling-uncover-molecular-mechanisms-high-risk-neuroblastoma-and-predict-disease-outcome02943nas a2200541   4500008004100000022001400041245008900055210006900144260000900213300001300222490000700235520138200242653001001624653000901634653001801643653002101661653001101682653002901693653003201722653002601754653001101780653001401791653002901805653000901834653001601843653001301859653002201872653001801894653001401912100002101926700003101947700002001978700002401998700002402022700002602046700001602072700001902088700001902107700002502126700002002151700001902171700002002190700002002210700002402230700002002254700001902274856010802293       2018                        eng d  a1932-620300aThe modular network structure of the mutational landscape of Acute Myeloid Leukemia.0 amodular network structure of the mutational landscape of Acute M  c2018  ae02029260 v133 a<p>Acute myeloid leukemia (AML) is associated with the sequential accumulation of acquired genetic alterations. Although at diagnosis cytogenetic alterations are frequent in AML, roughly 50% of patients present an apparently normal karyotype (NK), leading to a highly heterogeneous prognosis. Due to this significant heterogeneity, it has been suggested that different molecular mechanisms may trigger the disease with diverse prognostic implications. We performed whole-exome sequencing (WES) of tumor-normal matched samples of de novo AML-NK patients lacking mutations in NPM1, CEBPA or FLT3-ITD to identify new gene mutations with potential prognostic and therapeutic relevance to patients with AML. Novel candidate-genes, together with others previously described, were targeted resequenced in an independent cohort of 100 de novo AML patients classified in the cytogenetic intermediate-risk (IR) category. A mean of 4.89 mutations per sample were detected in 73 genes, 35 of which were mutated in more than one patient. After a network enrichment analysis, we defined a single in silico model and established a set of seed-genes that may trigger leukemogenesis in patients with normal karyotype. The high heterogeneity of gene mutations observed in AML patients suggested that a specific alteration could not be as essential as the interaction of deregulated pathways.</p>10aAdult10aAged10aCytodiagnosis10aExome Sequencing10aFemale10aGene Regulatory Networks10aGenetic Association Studies10aGenetic Heterogeneity10aHumans10aKaryotype10aLeukemia, Myeloid, Acute10aMale10aMiddle Aged10amutation10aNeoplasm Proteins10aNucleophosmin10aPrognosis1 aIbáñez, Mariam1 aCarbonell-Caballero, José1 aSuch, Esperanza1 aGarcía-Alonso, Luz1 aLiquori, Alessandro1 aLópez-Pavía, María1 aLLop, Marta1 aAlonso, Carmen1 aBarragán, Eva1 aGómez-Seguí, Inés1 aNeef, Alexander1 aHervás, David1 aMontesinos, Pau1 aSanz, Guillermo1 aSanz, Miguel, Angel1 aDopazo, Joaquin1 aCervera, José  uhttp://clinbioinfosspa.es/content/modular-network-structure-mutational-landscape-acute-myeloid-leukemia02800nas a2200445   4500008004100000022001400041245015700055210006900212260001600281300001600297490000600313520134500319653001001664653002501674653002601699653002001725653003801745653001301783653001501796653001101811653001801822653001601840653001601856653001401872653003501886100003001921700002401951700002201975700002601997700002902023700002202052700002602074700002502100700002402125700002102149700002002170700001802190700001702208856012902225       2017                        eng d  a1949-255300aGenomic expression differences between cutaneous cells from red hair color individuals and black hair color individuals based on bioinformatic analysis.0 aGenomic expression differences between cutaneous cells from red   c2017 Feb 14  a11589-115990 v83 a<p>The MC1R gene plays a crucial role in pigmentation synthesis. Loss-of-function MC1R variants, which impair protein function, are associated with red hair color (RHC) phenotype and increased skin cancer risk. Cultured cutaneous cells bearing loss-of-function MC1R variants show a distinct gene expression profile compared to wild-type MC1R cultured cutaneous cells. We analysed the gene signature associated with RHC co-cultured melanocytes and keratinocytes by Protein-Protein interaction (PPI) network analysis to identify genes related with non-functional MC1R variants. From two detected networks, we selected 23 nodes as hub genes based on topological parameters. Differential expression of hub genes was then evaluated in healthy skin biopsies from RHC and black hair color (BHC) individuals. We also compared gene expression in melanoma tumors from individuals with RHC versus BHC. Gene expression in normal skin from RHC cutaneous cells showed dysregulation in 8 out of 23 hub genes (CLN3, ATG10, WIPI2, SNX2, GABARAPL2, YWHA, PCNA and GBAS). Hub genes did not differ between melanoma tumors in RHC versus BHC individuals. The study suggests that healthy skin cells from RHC individuals present a constitutive genomic deregulation associated with the red hair phenotype and identify novel genes involved in melanocyte biology.</p>10aAdult10aCoculture Techniques10aComputational Biology10agene expression10aGenetic Predisposition to Disease10aGenomics10aHair Color10aHumans10aKeratinocytes10aMelanocytes10aMiddle Aged10aPhenotype10aReceptor, Melanocortin, Type 11 aPuig-Butille, Joan, Anton1 aGimenez-Xavier, Pol1 aVisconti, Alessia1 aNsengimana, Jérémie1 aGarcia-Garcia, Francisco1 aTell-Marti, Gemma1 aEscamez, Maria, José1 aNewton-Bishop, Julia1 aBataille, Veronique1 aDel Rio, Marcela1 aDopazo, Joaquin1 aFalchi, Mario1 aPuig, Susana  uhttp://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=14140&path%5B%5D=4509401431nas a2200481   4500008004100000022001400041245007200055210006900127260001600196300001400212490000800226653000900234653002400243653003700267653003400304653001900338653001000357653002900367653001100396653002200407653002800429653001100457653001600468653001300484100002100497700002100518700002800539700002700567700002600594700002000620700002000640700002000660700002900680700002000709700002600729700002800755700002200783700002400805700002000829700002100849700002500870856005400895       2017                        eng d  a1533-440600aGGPS1 Mutation and Atypical Femoral Fractures with Bisphosphonates.0 aGGPS1 Mutation and Atypical Femoral Fractures with Bisphosphonat  c2017 May 04  a1794-17950 v37610aAged10aAmino Acid Sequence10aBone Density Conservation Agents10aDimethylallyltranstransferase10aDiphosphonates10aExome10aFarnesyltranstransferase10aFemale10aFemoral Fractures10aGeranyltranstransferase10aHumans10aMiddle Aged10amutation1 aRoca-Ayats, Neus1 aBalcells, Susana1 aGarcia-Giralt, Natàlia1 aFalcó-Mascaró, Maite1 aMartínez-Gil, Núria1 aAbril, Josep, F1 aUrreizti, Roser1 aDopazo, Joaquin1 aQuesada-Gómez, José, M1 aNogués, Xavier1 aMellibovsky, Leonardo1 aPrieto-Alhambra, Daniel1 aDunford, James, E1 aJavaid, Muhammad, K1 aRussell, Graham1 aGrinberg, Daniel1 aDíez-Pérez, Adolfo  uhttp://www.nejm.org/doi/full/10.1056/NEJMc161280403363nas a2200241   4500008004100000022001400041245008900055210006900144260001600213300000800229490000700237520258700244653002102831653001102852653002902863653002802892653001102920653002402931653001302955100002002968700001702988856011603005       2017                        eng d  a1752-050900aGraph-theoretical comparison of normal and tumor networks in identifying BRCA genes.0 aGraphtheoretical comparison of normal and tumor networks in iden  c2017 Nov 22  a1100 v113 a<p><b>BACKGROUND: </b>Identification of driver genes related to certain types of cancer is an important research topic. Several systems biology approaches have been suggested, in particular for the identification of breast cancer (BRCA) related genes. Such approaches usually rely on differential gene expression and/or mutational landscape data. In some cases interaction network data is also integrated to identify cancer-related modules computationally.</p><p><b>RESULTS: </b>We provide a framework for the comparative graph-theoretical analysis of networks integrating the relevant gene expression, mutations, and potein-protein interaction network data. The comparisons involve a graph-theoretical analysis of normal and tumor network pairs across all instances of a given set of breast cancer samples. The network measures under consideration are based on appropriate formulations of various centrality measures: betweenness, clustering coefficients, degree centrality, random walk distances, graph-theoretical distances, and Jaccard index centrality.</p><p><b>CONCLUSIONS: </b>Among all the studied centrality-based graph-theoretical properties, we show that a betweenness-based measure differentiates BRCA genes across all normal versus tumor network pairs, than the rest of the popular centrality-based measures. The AUROC and AUPR values of the gene lists ordered with respect to the measures under study as compared to NCBI BioSystems pathway and the COSMIC database of cancer genes are the largest with the betweenness-based differentiation, followed by the measure based on degree centrality. In order to test the robustness of the suggested measures in prioritizing cancer genes, we further tested the two most promising measures, those based on betweenness and degree centralities, on randomly rewired networks. We show that both measures are quite resilient to noise in the input interaction network. We also compared the same measures against a state-of-the-art alternative disease gene prioritization method, MUFFFINN. We show that both our graph-theoretical measures outperform MUFFINN prioritizations in terms of ROC and precions/recall analysis. Finally, we filter the ordered list of the best measure, the betweenness-based differentiation, via a maximum-weight independent set formulation and investigate the top 50 genes in regards to literature verification. We show that almost all genes in the list are verified by the breast cancer literature and three genes are presented as novel genes that may potentialy be BRCA-related but missing in literature.</p>10aBreast Neoplasms10aFemale10aGene Regulatory Networks10aGenes, Tumor Suppressor10aHumans10aModels, Theoretical10amutation1 aDopazo, Joaquin1 aErten, Cesim  uhttp://clinbioinfosspa.es/content/graph-theoretical-comparison-normal-and-tumor-networks-identifying-brca-genes02299nas a2200361   4500008004100000022001400041245004600055210004400101260001600145300001400161490000700175520132500182653002201507653001801529653001101547653001301558653001301571653002801584100001801612700001701630700002101647700002301668700002301691700002201714700001601736700001701752700001901769700001801788700002001806700002001826700002001846856007101866       2017                        eng d  a1362-496200aHGVA: the Human Genome Variation Archive.0 aHGVA the Human Genome Variation Archive  c2017 Jul 03  aW189-W1940 v453 a<p>High-profile genomic variation projects like the 1000 Genomes project or the Exome Aggregation Consortium, are generating a wealth of human genomic variation knowledge which can be used as an essential reference for identifying disease-causing genotypes. However, accessing these data, contrasting the various studies and integrating those data in downstream analyses remains cumbersome. The Human Genome Variation Archive (HGVA) tackles these challenges and facilitates access to genomic data for key reference projects in a clean, fast and integrated fashion. HGVA provides an efficient and intuitive web-interface for easy data mining, a comprehensive RESTful API and client libraries in Python, Java and JavaScript for fast programmatic access to its knowledge base. HGVA calculates population frequencies for these projects and enriches their data with variant annotation provided by CellBase, a rich and fast annotation solution. HGVA serves as a proof-of-concept of the genome analysis developments being carried out by the University of Cambridge together with UK's 100 000 genomes project and the National Institute for Health Research BioResource Rare-Diseases, in particular, deploying open-source for Computational Biology (OpenCB) software platform for storing and analyzing massive genomic datasets.</p>10aGenetic Variation10aGenome, Human10aHumans10aInternet10aSoftware10aUser-Computer Interface1 aLopez, Javier1 aColl, Jacobo1 aHaimel, Matthias1 aKandasamy, Swaathi1 aTárraga, Joaquín1 aFurio-Tari, Pedro1 aBari, Wasim1 aBleda, Marta1 aRueda, Antonio1 aGräf, Stefan1 aRendon, Augusto1 aDopazo, Joaquin1 aMedina, Ignacio  uhttps://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkx44502079nas a2200313   4500008004100000022001400041245012900055210006900184260001600253300001400269490000600283520099600289653002601285653002001311653002901331653001101360653001301371653001401384653002301398653002701421653002401448100002201472700001801494700001901512700002401531700003101555700002001586856015901606       2017                        eng d  a1949-255300aHigh throughput estimation of functional cell activities reveals disease mechanisms and predicts relevant clinical outcomes.0 aHigh throughput estimation of functional cell activities reveals  c2017 Jan 17  a5160-51780 v83 a<p>Understanding the aspects of the cell functionality that account for disease or drug action mechanisms is a main challenge for precision medicine. Here we propose a new method that models cell signaling using biological knowledge on signal transduction. The method recodes individual gene expression values (and/or gene mutations) into accurate measurements of changes in the activity of signaling circuits, which ultimately constitute high-throughput estimations of cell functionalities caused by gene activity within the pathway. Moreover, such estimations can be obtained either at cohort-level, in case/control comparisons, or personalized for individual patients. The accuracy of the method is demonstrated in an extensive analysis involving 5640 patients from 12 different cancer types. Circuit activity measurements not only have a high diagnostic value but also can be related to relevant disease outcomes such as survival, and can be used to assess therapeutic interventions.</p>10aComputational Biology10agene expression10aGene Regulatory Networks10aHumans10amutation10aNeoplasms10aPrecision Medicine10aSequence Analysis, RNA10aSignal Transduction1 aHidalgo, Marta, R1 aCubuk, Cankut1 aAmadoz, Alicia1 aSalavert, Francisco1 aCarbonell-Caballero, José1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/high-throughput-estimation-functional-cell-activities-reveals-disease-mechanisms-and-predicts-relevant-clinical-outcomes02561nas a2200541   4500008004100000022001400041245008600055210006900141260001300210300001200223490000700235520094000242653002801182653001201210653002801222653001001250653004201260653001301302653001101315653003101326653000901357653001301366653001401379653003301393653002801426100002201454700001701476700002501493700003201518700002201550700001801572700002101590700002001611700002401631700003401655700001901689700002001708700002901728700002501757700001901782700002001801700001901821700001801840700001701858700001901875700001901894856010601913       2017                        eng d  a1098-100400aMutations in TRAPPC11 are associated with a congenital disorder of glycosylation.0 aMutations in TRAPPC11 are associated with a congenital disorder   c2017 Feb  a148-1510 v383 a<p>Congenital disorders of glycosylation (CDG) are a heterogeneous and rapidly growing group of diseases caused by abnormal glycosylation of proteins and/or lipids. Mutations in genes involved in the homeostasis of the endoplasmic reticulum (ER), the Golgi apparatus (GA), and the vesicular trafficking from the ER to the ER-Golgi intermediate compartment (ERGIC) have been found to be associated with CDG. Here, we report a patient with defects in both N- and O-glycosylation combined with a delayed vesicular transport in the GA due to mutations in TRAPPC11, a subunit of the TRAPPIII complex. TRAPPIII is implicated in the anterograde transport from the ER to the ERGIC as well as in the vesicle export from the GA. This report expands the spectrum of genetic alterations associated with CDG, providing new insights for the diagnosis and the understanding of the physiopathological mechanisms underlying glycosylation disorders.</p>10aAbnormalities, Multiple10aAlleles10aAmino Acid Substitution10aBrain10aCongenital Disorders of Glycosylation10aGenotype10aHumans10aMagnetic Resonance Imaging10aMale10amutation10aPhenotype10aVesicular Transport Proteins10aWhole Genome Sequencing1 aMatalonga, Leslie1 aBravo, Miren1 aSerra-Peinado, Carla1 aGarcía-Pelegrí, Elisabeth1 aUgarteburu, Olatz1 aVidal, Silvia1 aLlambrich, Maria1 aQuintana, Ester1 aFuster-Jorge, Pedro1 aGonzalez-Bravo, Maria, Nieves1 aBeltran, Sergi1 aDopazo, Joaquin1 aGarcia-Garcia, Francisco1 aFoulquier, François1 aMatthijs, Gert1 aMills, Philippa1 aRibes, Antonia1 aEgea, Gustavo1 aBriones, Paz1 aTort, Frederic1 aGirós, Marisa  uhttp://clinbioinfosspa.es/content/mutations-trappc11-are-associated-congenital-disorder-glycosylation02685nas a2200349   4500008004100000022001400041245011500055210006900170260001600239300001400255490000700269520162000276653001201896653002201908653001101930653001301941653001301954653001101967653002401978653002002002653003102022653001302053100003102066700001902097700002002116700002202136700001802158700001802176700002802194700002002222856009302242       2017                        eng d  a1367-481100aReference genome assessment from a population scale perspective: an accurate profile of variability and noise.0 aReference genome assessment from a population scale perspective   c2017 Nov 15  a3511-35170 v333 a<p><b>MOTIVATION: </b>Current plant and animal genomic studies are often based on newly assembled genomes that have not been properly consolidated. In this scenario, misassembled regions can easily lead to false-positive findings. Despite quality control scores are included within genotyping protocols, they are usually employed to evaluate individual sample quality rather than reference sequence reliability. We propose a statistical model that combines quality control scores across samples in order to detect incongruent patterns at every genomic region. Our model is inherently robust since common artifact signals are expected to be shared between independent samples over misassembled regions of the genome.</p><p><b>RESULTS: </b>The reliability of our protocol has been extensively tested through different experiments and organisms with accurate results, improving state-of-the-art methods. Our analysis demonstrates synergistic relations between quality control scores and allelic variability estimators, that improve the detection of misassembled regions, and is able to find strong artifact signals even within the human reference assembly. Furthermore, we demonstrated how our model can be trained to properly rank the confidence of a set of candidate variants obtained from new independent samples.</p><p><b>AVAILABILITY AND IMPLEMENTATION: </b>This tool is freely available at http://gitlab.com/carbonell/ces.</p><p><b>CONTACT: </b>jcarbonell.cipf@gmail.com or joaquin.dopazo@juntadeandalucia.es.</p><p><b>SUPPLEMENTARY INFORMATION: </b>Supplementary data are available at Bioinformatics online.</p>10aAnimals10aGenetic Variation10aGenome10aGenomics10aGenotype10aHumans10aModels, Statistical10aQuality Control10aReproducibility of Results10aSoftware1 aCarbonell-Caballero, José1 aAmadoz, Alicia1 aAlonso, Roberto1 aHidalgo, Marta, R1 aCubuk, Cankut1 aConesa, David1 aLópez-Quílez, Antonio1 aDopazo, Joaquin  uhttps://academic.oup.com/bioinformatics/article-lookup/doi/10.1093/bioinformatics/btx48201955nas a2200325   4500008004100000022001400041245009200055210006900147260001600216300000800232490000700240520091900247653001801166653002001184653002001204653004201224653001101266653001301277653002801290653002201318100002101340700002301361700002301384700002201407700002401429700002001453700001901473700002001492856011701512       2017                        eng d  a1471-210500aVISMapper: ultra-fast exhaustive cartography of viral insertion sites for gene therapy.0 aVISMapper ultrafast exhaustive cartography of viral insertion si  c2017 Sep 20  a4210 v183 a<p><b>BACKGROUND: </b>The possibility of integrating viral vectors to become a persistent part of the host genome makes them a crucial element of clinical gene therapy. However, viral integration has associated risks, such as the unintentional activation of oncogenes that can result in cancer. Therefore, the analysis of integration sites of retroviral vectors is a crucial step in developing safer vectors for therapeutic use.</p><p><b>RESULTS: </b>Here we present VISMapper, a vector integration site analysis web server, to analyze next-generation sequencing data for retroviral vector integration sites. VISMapper can be found at: http://vismapper.babelomics.org .</p><p><b>CONCLUSIONS: </b>Because it uses novel mapping algorithms VISMapper is remarkably faster than previous available programs. It also provides a useful graphical interface to analyze the integration sites found in the genomic context.</p>10aBase Sequence10aGenetic Therapy10aGenetic Vectors10aHigh-Throughput Nucleotide Sequencing10aHumans10aInternet10aUser-Computer Interface10aVirus Integration1 aJuanes, José, M1 aGallego, Asunción1 aTárraga, Joaquín1 aChaves, Felipe, J1 aMarin-Garcia, Pablo1 aMedina, Ignacio1 aArnau, Vicente1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/vismapper-ultra-fast-exhaustive-cartography-viral-insertion-sites-gene-therapy01692nas a2200337   4500008004100000022001400041245007000055210006800125260001300193300001100206490000700217520067700224653001300901653004200914653001100956653003200967653002700999653001801026100001401044700001601058700001701074700001801091700001901109700001601128700002301144700002301167700002601190700002501216700001401241856009901255       2016                        eng d  a1756-166300aHighly sensitive and ultrafast read mapping for RNA-seq analysis.0 aHighly sensitive and ultrafast read mapping for RNAseq analysis  c2016 Apr  a93-1000 v233 a<p>As sequencing technologies progress, the amount of data produced grows exponentially, shifting the bottleneck of discovery towards the data analysis phase. In particular, currently available mapping solutions for RNA-seq leave room for improvement in terms of sensitivity and performance, hindering an efficient analysis of transcriptomes by massive sequencing. Here, we present an innovative approach that combines re-engineering, optimization and parallelization. This solution results in a significant increase of mapping sensitivity over a wide range of read lengths and substantial shorter runtimes when compared with current RNA-seq mapping methods available.</p>10aGenomics10aHigh-Throughput Nucleotide Sequencing10aHumans10aSensitivity and Specificity10aSequence Analysis, RNA10aTranscriptome1 aMedina, I1 aTárraga, J1 aMartínez, H1 aBarrachina, S1 aCastillo, M, I1 aPaschall, J1 aSalavert-Torres, J1 aBlanquer-Espert, I1 aHernández-García, V1 aQuintana-Ortí, E, S1 aDopazo, J  uhttp://clinbioinfosspa.es/content/highly-sensitive-and-ultrafast-read-mapping-rna-seq-analysis02494nas a2200505   4500008004100000022001400041245008800055210006900143260001600212300000900228490000600237520111400243653001001357653000901367653002201376653002001398653001601418653001101434653001101445653000901456653001601465653003101481653002201512653002601534100002201560700001201582700001301594700001301607700001401620700002301634700001801657700001701675700002301692700002001715700002001735700001401755700001401769700001301783700001601796700001201812700001401824700001601838700001601854856011801870       2016                        eng d  a2158-318800aHuman DNA methylomes of neurodegenerative diseases show common epigenomic patterns.0 aHuman DNA methylomes of neurodegenerative diseases show common e  c2016 Jan 19  ae7180 v63 a<p>Different neurodegenerative disorders often show similar lesions, such as the presence of amyloid plaques, TAU-neurotangles and synuclein inclusions. The genetically inherited forms are rare, so we wondered whether shared epigenetic aberrations, such as those affecting DNA methylation, might also exist. The studied samples were gray matter samples from the prefrontal cortex of control and neurodegenerative disease-associated cases. We performed the DNA methylation analyses of Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease and Alzheimer-like neurodegenerative profile associated with Down's syndrome samples. The DNA methylation landscapes obtained show that neurodegenerative diseases share similar aberrant CpG methylation shifts targeting a defined gene set. Our findings suggest that neurodegenerative disorders might have similar pathogenetic mechanisms that subsequently evolve into different clinical entities. The identified aberrant DNA methylation changes can be used as biomarkers of the disorders and as potential new targets for the development of new therapies. </p>10aAdult10aAged10aAged, 80 and over10aDNA Methylation10aEpigenomics10aFemale10aHumans10aMale10aMiddle Aged10aneurodegenerative diseases10aPrefrontal Cortex10aTissue Array Analysis1 aSanchez-Mut, J, V1 aHeyn, H1 aVidal, E1 aMoran, S1 aSayols, S1 aDelgado-Morales, R1 aSchultz, M, D1 aAnsoleaga, B1 aGarcia-Esparcia, P1 aPons-Espinal, M1 ade Lagran, M, M1 aDopazo, J1 aRabano, A1 aAvila, J1 aDierssen, M1 aLott, I1 aFerrer, I1 aEcker, J, R1 aEsteller, M  uhttp://clinbioinfosspa.es/content/human-dna-methylomes-neurodegenerative-diseases-show-common-epigenomic-patterns03253nas a2200697   4500008004100000022001400041245013600055210006900191260001600260300001000276490000600286520117300292653000901465653001201474653002601486653002001512653001901532653003801551653001801589653002801607653001001635653001701645653001101662653003101673653002101704653002501725653001501750653001101765653000901776653000901785653001601794653003601810653003201846653001101878653002401889653003601913653002501949653001001974653002101984653002602005100001402031700002402045700001602069700001602085700001702101700002402118700002702142700002402169700002102193700001302214700002302227700001402250700002702264700002002291700002302311700001402334700002402348700001402372700001302386856015602399       2016                        eng d  a2045-232200aIdentification of the Photoreceptor Transcriptional Co-Repressor SAMD11 as Novel Cause of Autosomal Recessive Retinitis Pigmentosa.0 aIdentification of the Photoreceptor Transcriptional CoRepressor   c2016 Oct 13  a353700 v63 a<p>Retinitis pigmentosa (RP), the most frequent form of inherited retinal dystrophy is characterized by progressive photoreceptor degeneration. Many genes have been implicated in RP development, but several others remain to be identified. Using a combination of homozygosity mapping, whole-exome and targeted next-generation sequencing, we found a novel homozygous nonsense mutation in SAMD11 in five individuals diagnosed with adult-onset RP from two unrelated consanguineous Spanish families. SAMD11 is ortholog to the mouse major retinal SAM domain (mr-s) protein that is implicated in CRX-mediated transcriptional regulation in the retina. Accordingly, protein-protein network analysis revealed a significant interaction of SAMD11 with CRX. Immunoblotting analysis confirmed strong expression of SAMD11 in human retina. Immunolocalization studies revealed SAMD11 was detected in the three nuclear layers of the human retina and interestingly differential expression between cone and rod photoreceptors was observed. Our study strongly implicates SAMD11 as novel cause of RP playing an important role in the pathogenesis of human degeneration of photoreceptors.</p>10aAged10aAnimals10aCo-Repressor Proteins10aCodon, Nonsense10aCohort Studies10aComparative Genomic Hybridization10aConsanguinity10aDNA Mutational Analysis10aExome10aEye Proteins10aFemale10aGene Expression Regulation10aGenes, Recessive10aHomeodomain Proteins10aHomozygote10aHumans10aMale10aMice10aMiddle Aged10aPolymorphism, Single Nucleotide10aProtein Interaction Mapping10aRetina10aRetinal Dystrophies10aRetinal Rod Photoreceptor Cells10aRetinitis pigmentosa10aSpain10aTrans-Activators10aTranscription Factors1 aCorton, M1 aAvila-Fernández, A1 aCampello, L1 aSánchez, M1 aBenavides, B1 aLópez-Molina, M, I1 aFernández-Sánchez, L1 aSánchez-Alcudia, R1 ada Silva, L, R J1 aReyes, N1 aMartín-Garrido, E1 aZurita, O1 aSan José, Fernández-1 aPérez-Carro, R1 aGarcía-García, F1 aDopazo, J1 aGarcía-Sandoval, B1 aCuenca, N1 aAyuso, C  uhttp://clinbioinfosspa.es/content/identification-photoreceptor-transcriptional-co-repressor-samd11-novel-cause-autosomal-recessive-retinitis-pigmentosa02756nas a2200397   4500008004100000022001400041245012200055210006900177260001600246300001000262490000600272520143100278653001201709653002401721653003101745653002801776653001701804653001701821653003201838653002601870653002001896653004201916653001101958653001301969653001401982653002401996100002302020700002802043700002502071700003302096700003602129700002002165700001902185700002502204856012902229       2016                        eng d  a2045-232200aImproving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel.0 aImproving the management of Inherited Retinal Dystrophies by tar  c2016 Apr 01  a239100 v63 a<p>Next-generation sequencing (NGS) has overcome important limitations to the molecular diagnosis of Inherited Retinal Dystrophies (IRD) such as the high clinical and genetic heterogeneity and the overlapping phenotypes. The purpose of this study was the identification of the genetic defect in 32 Spanish families with different forms of IRD. With that aim, we implemented a custom NGS panel comprising 64 IRD-associated genes in our population, and three disease-associated intronic regions. A total of 37 pathogenic mutations (14 novels) were found in 73% of IRD patients ranging from 50% for autosomal dominant cases, 75% for syndromic cases, 83% for autosomal recessive cases, and 100% for X-linked cases. Additionally, unexpected phenotype-genotype correlations were found in 6 probands, which led to the refinement of their clinical diagnoses. Furthermore, intra- and interfamilial phenotypic variability was observed in two cases. Moreover, two cases unsuccessfully analysed by exome sequencing were resolved by applying this panel. Our results demonstrate that this hypothesis-free approach based on frequently mutated, population-specific loci is highly cost-efficient for the routine diagnosis of this heterogeneous condition and allows the unbiased analysis of a miscellaneous cohort. The molecular information found here has aid clinical diagnosis and has improved genetic counselling and patient management. </p>10aAlleles10aComputer Simulation10aDNA Copy Number Variations10aDNA Mutational Analysis10aEye Proteins10aGene Library10aGenetic Association Studies10aGenetic Heterogeneity10aGenetic Therapy10aHigh-Throughput Nucleotide Sequencing10aHumans10amutation10aPhenotype10aRetinal Dystrophies1 aBravo-Gil, Nereida1 aMéndez-Vidal, Cristina1 aRomero-Pérez, Laura1 adel Pozo, María, González-1 ade la Rúa, Enrique, Rodríguez1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo  uhttp://clinbioinfosspa.es/content/improving-management-inherited-retinal-dystrophies-targeted-sequencing-population-specific02430nas a2200289   4500008004100000022001400041245005500055210005400110260001600164300001200180490000700192520155100199653002601750653003001776653001801806653002901824653004201853653001101895653001401906653001401920653003101934100002901965700002201994700002002016700002002036856008402056       2016                        eng d  a1367-481100aIntegrated gene set analysis for microRNA studies.0 aIntegrated gene set analysis for microRNA studies  c2016 Sep 15  a2809-160 v323 a<p><b>MOTIVATION: </b>Functional interpretation of miRNA expression data is currently done in a three step procedure: select differentially expressed miRNAs, find their target genes, and carry out gene set overrepresentation analysis Nevertheless, major limitations of this approach have already been described at the gene level, while some newer arise in the miRNA scenario.Here, we propose an enhanced methodology that builds on the well-established gene set analysis paradigm. Evidence for differential expression at the miRNA level is transferred to a gene differential inhibition score which is easily interpretable in terms of gene sets or pathways. Such transferred indexes account for the additive effect of several miRNAs targeting the same gene, and also incorporate cancellation effects between cases and controls. Together, these two desirable characteristics allow for more accurate modeling of regulatory processes.</p><p><b>RESULTS: </b>We analyze high-throughput sequencing data from 20 different cancer types and provide exhaustive reports of gene and Gene Ontology-term deregulation by miRNA action.</p><p><b>AVAILABILITY AND IMPLEMENTATION: </b>The proposed methodology was implemented in the Bioconductor library mdgsa http://bioconductor.org/packages/mdgsa For the purpose of reproducibility all of the scripts are available at https://github.com/dmontaner-papers/gsa4mirna</p><p><b>CONTACT: </b>: david.montaner@gmail.com</p><p><b>SUPPLEMENTARY INFORMATION: </b>Supplementary data are available at Bioinformatics online.</p>10aComputational Biology10aGene Expression Profiling10aGene ontology10aGene Regulatory Networks10aHigh-Throughput Nucleotide Sequencing10aHumans10aMicroRNAs10aNeoplasms10aReproducibility of Results1 aGarcia-Garcia, Francisco1 aPanadero, Joaquin1 aDopazo, Joaquin1 aMontaner, David  uhttp://clinbioinfosspa.es/content/integrated-gene-set-analysis-microrna-studies02859nas a2200433   4500008004100000022001400041245013500055210006900190260000900259300001300268490000700281520145800288653001001746653002901756653001801785653001101803653001901814653003501833653001301868653001801881653003601899653003101935100002101966700003101987700002402018700002002042700002902062700001902091700001902110700002602129700001602155700001902171700002502190700002002215700002002235700002002255700001902275856013102294       2016                        eng d  a1932-620300aThe Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations.0 aMutational Landscape of Acute Promyelocytic Leukemia Reveals an   c2016  ae01483460 v113 a<p>Preliminary Acute Promyelocytic Leukemia (APL) whole exome sequencing (WES) studies have identified a huge number of somatic mutations affecting more than a hundred different genes mainly in a non-recurrent manner, suggesting that APL is a heterogeneous disease with secondary relevant changes not yet defined. To extend our knowledge of subtle genetic alterations involved in APL that might cooperate with PML/RARA in the leukemogenic process, we performed a comprehensive analysis of somatic mutations in APL combining WES with sequencing of a custom panel of targeted genes by next-generation sequencing. To select a reduced subset of high confidence candidate driver genes, further in silico analysis were carried out. After prioritization and network analysis we found recurrent deleterious mutations in 8 individual genes (STAG2, U2AF1, SMC1A, USP9X, IKZF1, LYN, MYCBP2 and PTPN11) with a strong potential of being involved in APL pathogenesis. Our network analysis of multiple mutations provides a reliable approach to prioritize genes for additional analysis, improving our knowledge of the leukemogenesis interactome. Additionally, we have defined a functional module in the interactome of APL. The hypothesis is that the number, or the specific combinations, of mutations harbored in each patient might not be as important as the disturbance caused in biological key functions, triggered by several not necessarily recurrent mutations. </p>10aExome10aGene Regulatory Networks10aGenome, Human10aHumans10aINDEL Mutation10aLeukemia, Promyelocytic, Acute10amutation10aMutation Rate10aPolymorphism, Single Nucleotide10aReproducibility of Results1 aIbáñez, Mariam1 aCarbonell-Caballero, José1 aGarcía-Alonso, Luz1 aSuch, Esperanza1 aJiménez-Almazán, Jorge1 aVidal, Enrique1 aBarragán, Eva1 aLópez-Pavía, María1 aLLop, Marta1 aMartín, Iván1 aGómez-Seguí, Inés1 aMontesinos, Pau1 aSanz, Miguel, A1 aDopazo, Joaquin1 aCervera, José  uhttp://clinbioinfosspa.es/content/mutational-landscape-acute-promyelocytic-leukemia-reveals-interacting-network-co-occurrences03502nas a2200517   4500008004100000022001400041245007400055210006900129260001300198300001000211490000800221520209300229653001002322653000902332653001202341653001002353653003202363653001102395653002002406653001102426653001102437653000902448653000902457653001602466653001302482653001302495653001402508653001802522653001602540653002602556653001602582100002002598700001902618700002902637700001802666700001902684700002502703700002402728700003102752700001802783700002002801700002202821700002002843700002102863856010002884       2016                        eng d  a1460-215600aMutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease.0 aMutations in the MORC2 gene cause axonal CharcotMarieTooth disea  c2016 Jan  a62-720 v1393 a<p>Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p.R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p.R190W mutation and another patient that harboured a MORC2 p.S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a new pathogenic mechanism to the long list of causes of Charcot-Marie-Tooth disease. </p>10aAdult10aAged10aAnimals10aAxons10aCharcot-Marie-Tooth Disease10aFemale10agene expression10aHumans10aInfant10aMale10aMice10aMiddle Aged10amutation10aPedigree10aPhenotype10aSciatic Nerve10aSural Nerve10aTranscription Factors10aYoung Adult1 aSevilla, Teresa1 aLupo, Vincenzo1 aMartínez-Rubio, Dolores1 aSancho, Paula1 aSivera, Rafael1 aChumillas, María, J1 aGarcía-Romero, Mar1 aPascual-Pascual, Samuel, I1 aMuelas, Nuria1 aDopazo, Joaquin1 aVílchez, Juan, J1 aPalau, Francesc1 aEspinós, Carmen  uhttp://clinbioinfosspa.es/content/mutations-morc2-gene-cause-axonal-charcot-marie-tooth-disease02421nas a2200325   4500008004100000022001400041245006600055210006400121260001300185300001000198490000700208520140200215653002501617653003401642653003701676653001101713653002201724653002101746653003601767653002301803100002101826700001701847700002001864700002201884700003201906700001901938700002201957700002101979856009502000       2016                        eng d  a2363-891500aProgress in pharmacogenetics: consortiums and new strategies.0 aProgress in pharmacogenetics consortiums and new strategies  c2016 Mar  a17-230 v313 a<p>Pharmacogenetics (PGx), as a field dedicated to achieving the goal of personalized medicine (PM), is devoted to the study of genes involved in inter-individual response to drugs. Due to its nature, PGx requires access to large samples; therefore, in order to progress, the formation of collaborative consortia seems to be crucial. Some examples of this collective effort are the European Society of Pharmacogenomics and personalized Therapy and the Ibero-American network of Pharmacogenetics. As an emerging field, one of the major challenges that PGx faces is translating their discoveries from research bench to bedside. The development of genomic high-throughput technologies is generating a revolution and offers the possibility of producing vast amounts of genome-wide single nucleotide polymorphisms for each patient. Moreover, there is a need of identifying and replicating associations of new biomarkers, and, in addition, a greater effort must be invested in developing regulatory organizations to accomplish a correct standardization. In this review, we outline the current progress in PGx using examples to highlight both the importance of polymorphisms and the research strategies for their detection. These concepts need to be applied together with a proper dissemination of knowledge to improve clinician and patient understanding, in a multidisciplinary team-based approach. </p>10aCooperative Behavior10aGenome-Wide Association Study10aHigh-Throughput Screening Assays10aHumans10aPatient Care Team10apharmacogenetics10aPolymorphism, Single Nucleotide10aPrecision Medicine1 aMaroñas, Olalla1 aLatorre, Ana1 aDopazo, Joaquin1 aPirmohamed, Munir1 aRodríguez-Antona, Cristina1 aSiest, Gérard1 aCarracedo, Ángel1 aLLerena, Adrián  uhttp://clinbioinfosspa.es/content/progress-pharmacogenetics-consortiums-and-new-strategies02956nas a2200505   4500008004100000022001400041245008800055210006900143260001300212300001000225490000900235520151700244653001501761653001701776653001001793653002101803653002101824653001001845653001101855653004201866653001101908653001101919653002801930653000901958653001301967653001301980653001401993653001402007653002302021100002002044700002102064700001902085700002902104700002302133700002202156700002202178700001902200700001902219700002002238700001702258700002302275700002102298700002102319856011002340       2016                        eng d  a1552-483300aScreening of CD96 and ASXL1 in 11 patients with Opitz C or Bohring-Opitz syndromes.0 aScreening of CD96 and ASXL1 in 11 patients with Opitz C or Bohri  c2016 Jan  a24-310 v170A3 a<p>Opitz C trigonocephaly (or Opitz C syndrome, OTCS) and Bohring-Opitz syndrome (BOS or C-like syndrome) are two rare genetic disorders with phenotypic overlap. The genetic causes of these diseases are not understood. However, two genes have been associated with OTCS or BOS with dominantly inherited de novo mutations. Whereas CD96 has been related to OTCS (one case) and to BOS (one case), ASXL1 has been related to BOS only (several cases). In this study we analyze CD96 and ASXL1 in a group of 11 affected individuals, including 2 sibs, 10 of them were diagnosed with OTCS, and one had a BOS phenotype. Exome sequences were available on six patients with OTCS and three parent pairs. Thus, we could analyze the CD96 and ASXL1 sequences in these patients bioinformatically. Sanger sequencing of all exons of CD96 and ASXL1 was carried out in the remaining patients. Detailed scrutiny of the sequences and assessment of variants allowed us to exclude putative pathogenic and private mutations in all but one of the patients. In this patient (with BOS) we identified a de novo mutation in ASXL1 (c.2100dupT). By nature and location within the gene, this mutation resembles those previously described in other BOS patients and we conclude that it may be responsible for the condition. Our results indicate that in 10 of 11, the disease (OTCS or BOS) cannot be explained by small changes in CD96 or ASXL1. However, the cohort is too small to make generalizations about the genetic etiology of these diseases.</p>10aAdolescent10aAntigens, CD10aChild10aChild, Preschool10aCraniosynostoses10aExome10aFemale10aHigh-Throughput Nucleotide Sequencing10aHumans10aInfant10aIntellectual Disability10aMale10amutation10aPedigree10aPhenotype10aPrognosis10aRepressor Proteins1 aUrreizti, Roser1 aRoca-Ayats, Neus1 aTrepat, Judith1 aGarcia-Garcia, Francisco1 aAlemán, Alejandro1 aOrteschi, Daniela1 aMarangi, Giuseppe1 aNeri, Giovanni1 aOpitz, John, M1 aDopazo, Joaquin1 aCormand, Bru1 aVilageliu, Lluïsa1 aBalcells, Susana1 aGrinberg, Daniel  uhttp://clinbioinfosspa.es/content/screening-cd96-and-asxl1-11-patients-opitz-c-or-bohring-opitz-syndromes02605nas a2200397   4500008004100000022001400041245017300055210006900228260001600297300001300313490000600326520129300332653001001625653000901635653002201644653003501666653002401701653001101725653001101736653001901747653000901766653001701775653001601792653004301808100003001851700002801881700002501909700002901934700001501963700002101978700001601999700002002015700001802035700002702053856012702080       2016                        eng d  a1949-255300aSerum metabolomic profiling facilitates the non-invasive identification of metabolic biomarkers associated with the onset and progression of non-small cell lung cancer.0 aSerum metabolomic profiling facilitates the noninvasive identifi  c2016 Mar 15  a12904-160 v73 a<p>Lung cancer (LC) is responsible for most cancer deaths. One of the main factors contributing to the lethality of this disease is the fact that a large proportion of patients are diagnosed at advanced stages when a clinical intervention is unlikely to succeed. In this study, we evaluated the potential of metabolomics by 1H-NMR to facilitate the identification of accurate and reliable biomarkers to support the early diagnosis and prognosis of non-small cell lung cancer (NSCLC).We found that the metabolic profile of NSCLC patients, compared with healthy individuals, is characterized by statistically significant changes in the concentration of 18 metabolites representing different amino acids, organic acids and alcohols, as well as different lipids and molecules involved in lipid metabolism. Furthermore, the analysis of the differences between the metabolic profiles of NSCLC patients at different stages of the disease revealed the existence of 17 metabolites involved in metabolic changes associated with disease progression.Our results underscore the potential of metabolomics profiling to uncover pathophysiological mechanisms that could be useful to objectively discriminate NSCLC patients from healthy individuals, as well as between different stages of the disease. </p>10aAdult10aAged10aBiomarkers, Tumor10aCarcinoma, Non-Small-Cell Lung10aDisease Progression10aFemale10aHumans10aLung Neoplasms10aMale10ametabolomics10aMiddle Aged10aProton Magnetic Resonance Spectroscopy1 aPuchades-Carrasco, Leonor1 aJantus-Lewintre, Eloisa1 aPérez-Rambla, Clara1 aGarcia-Garcia, Francisco1 aLucas, Rut1 aCalabuig, Silvia1 aBlasco, Ana1 aDopazo, Joaquin1 aCamps, Carlos1 aPineda-Lucena, Antonio  uhttp://clinbioinfosspa.es/content/serum-metabolomic-profiling-facilitates-non-invasive-identification-metabolic-biomarkers02962nas a2200529   4500008004100000022001400041245011800055210006900173260001200242300001400254490000800268520135400276653001501630653001001645653001201655653002701667653002101694653002401715653001001739653002101749653002801770653001001798653001101808653003501819653002201854653004201876653001101918653003301929653001301962653002601975653003702001653002502038653001802063100002202081700001902103700001802122700001902140700001502159700001802174700001902192700001902211700002002230700001802250700002202268700002002290856012202310       2016                        eng d  a1432-120300aWhole exome sequencing of Rett syndrome-like patients reveals the mutational diversity of the clinical phenotype.0 aWhole exome sequencing of Rett syndromelike patients reveals the  c2016 12  a1343-13540 v1353 a<p>Classical Rett syndrome (RTT) is a neurodevelopmental disorder where most of cases carry MECP2 mutations. Atypical RTT variants involve mutations in CDKL5 and FOXG1. However, a subset of RTT patients remains that do not carry any mutation in the described genes. Whole exome sequencing was carried out in a cohort of 21 female probands with clinical features overlapping with those of RTT, but without mutations in the customarily studied genes. Candidates were functionally validated by assessing the appearance of a neurological phenotype in Caenorhabditis elegans upon disruption of the corresponding ortholog gene. We detected pathogenic variants that accounted for the RTT-like phenotype in 14 (66.6 %) patients. Five patients were carriers of mutations in genes already known to be associated with other syndromic neurodevelopmental disorders. We determined that the other patients harbored mutations in genes that have not previously been linked to RTT or other neurodevelopmental syndromes, such as the ankyrin repeat containing protein ANKRD31 or the neuronal acetylcholine receptor subunit alpha-5 (CHRNA5). Furthermore, worm assays demonstrated that mutations in the studied candidate genes caused locomotion defects. Our findings indicate that mutations in a variety of genes contribute to the development of RTT-like phenotypes.</p>10aAdolescent10aAdult10aAnimals10aCaenorhabditis elegans10aCarrier Proteins10aCell Cycle Proteins10aChild10aChild, Preschool10aDNA Mutational Analysis10aExome10aFemale10aForkhead Transcription Factors10aGenetic Variation10aHigh-Throughput Nucleotide Sequencing10aHumans10aMethyl-CpG-Binding Protein 210amutation10aNerve Tissue Proteins10aProtein Serine-Threonine Kinases10aReceptors, Nicotinic10aRett Syndrome1 aLucariello, Mario1 aVidal, Enrique1 aVidal, Silvia1 aSaez, Mauricio1 aRoa, Laura1 aHuertas, Dori1 aPineda, Mercè1 aDalfó, Esther1 aDopazo, Joaquin1 aJurado, Paola1 aArmstrong, Judith1 aEsteller, Manel  uhttp://clinbioinfosspa.es/content/whole-exome-sequencing-rett-syndrome-patients-reveals-mutational-diversity-clinical03277nas a2200445   4500008004100000022001400041245015900055210006900214260001600283300000900299490000800308520183200316653001002148653000902158653001102167653004102178653002302219653003002242653004602272653001802318653003402336653001702370653001102387653001602398653002002414653001302434653004402447653001202491653003402503653002402537100002302561700002502584700001602609700002302625700001302648700001402661700001602675700001302691856012702704       2015                        eng d  a1879-003800aDeregulation of key signaling pathways involved in oocyte maturation in FMR1 premutation carriers with Fragile X-associated primary ovarian insufficiency.0 aDeregulation of key signaling pathways involved in oocyte matura  c2015 Oct 15  a52-70 v5713 a<p>FMR1 premutation female carriers are at risk for Fragile X-associated primary ovarian insufficiency (FXPOI). Insights from knock-in mouse model have recently demonstrated that FXPOI is due to an increased rate of follicle depletion or an impaired development of the growing follicles. Molecular mechanisms responsible for this reduced viability are still unknown. In an attempt to provide new data on the mechanisms that lead to FXPOI, we report the first investigation involving transcription profiling of total blood from FMR1 premutation female carriers with and without FXPOI. A total of 16 unrelated female individuals (6 FMR1 premutated females with FXPOI; 6 FMR1 premutated females without FXPOI; and 4 no-FXPOI females) were studied by whole human genome oligonucleotide microarray (Agilent Technologies). Fold change analysis did not show any genes with significant differential gene expression. However, functional profiling by gene set analysis showed large number of statistically significant deregulated GO annotations as well as numerous KEGG pathways in FXPOI females. These results suggest that the impairment of fertility in these females might be due to a generalized deregulation of key signaling pathways involved in oocyte maturation. In particular, the vasoendotelial growth factor signaling, the inositol phosphate metabolism, the cell cycle, and the MAPK signaling pathways were found to be down-regulated in FXPOI females. Furthermore, a high statistical enrichment of biological processes involved in cell death and survival were found deregulated among FXPOI females. Our results provide new strategic approaches to further investigate the molecular mechanisms and potential therapeutic targets for FXPOI not focused in a single gene but rather in the set of genes involved in these pathways. </p>10aAdult10aAged10aFemale10aFragile X Mental Retardation Protein10aFragile X Syndrome10aGene Expression Profiling10aGene Expression Regulation, Developmental10aGene ontology10aGenome-Wide Association Study10aHeterozygote10aHumans10aMiddle Aged10aModels, Genetic10amutation10aOligonucleotide Array Sequence Analysis10aOocytes10aPrimary Ovarian Insufficiency10aSignal Transduction1 aAlvarez-Mora, M, I1 aRodriguez-Revenga, L1 aMadrigal, I1 aGarcía-García, F1 aDuran, M1 aDopazo, J1 aEstivill, X1 aMilà, M  uhttp://clinbioinfosspa.es/content/deregulation-key-signaling-pathways-involved-oocyte-maturation-fmr1-premutation-carriers02461nas a2200445   4500008004100000022001400041245006900055210006200124260001300186300001200199490000700211520128200218653001001500653000901510653002201519653001001541653003201551653003601583653001001619653001101629653001101640653000901651653001601660653001301676653001301689653001401702653003001716653001601746100001501762700001401777700002301791700001201814700002001826700001501846700001401861700001901875700001301894700001601907856009201923       2015                        eng d  a1468-133100aThe EGR2 gene is involved in axonal Charcot-Marie-Tooth disease.0 aEGR2 gene is involved in axonal CharcotMarieTooth disease  c2015 Dec  a1548-550 v223 a<p><b>BACKGROUND AND PURPOSE: </b>A three-generation family affected by axonal Charcot-Marie-Tooth disease (CMT) was investigated with the aim of discovering genetic defects and to further characterize the phenotype.</p><p><b>METHODS: </b>The clinical, nerve conduction studies and muscle magnetic resonance images of the patients were reviewed. A whole exome sequencing was performed and the changes were investigated by genetic studies, in silico analysis and luciferase reporter assays.</p><p><b>RESULTS: </b>A novel c.1226G>A change (p.R409Q) in the EGR2 gene was identified. Patients presented with a typical, late-onset axonal CMT phenotype with variable severity that was confirmed in the ancillary tests. The in silico studies showed that the residue R409 is an evolutionary conserved amino acid. The p.R409Q mutation, which is predicted as probably damaging, would alter the conformation of the protein slightly and would cause a decrease of gene expression.</p><p><b>CONCLUSIONS: </b>This is the first report of an EGR2 mutation presenting as an axonal CMT phenotype with variable severity. This study broadens the phenotype of the EGR2-related neuropathies and suggests that the genetic testing of patients suffering from axonal CMT should include the EGR2 gene.</p>10aAdult10aAged10aAged, 80 and over10aAxons10aCharcot-Marie-Tooth Disease10aEarly Growth Response Protein 210aExome10aFemale10aHumans10aMale10aMiddle Aged10amutation10aPedigree10aPhenotype10aSeverity of Illness Index10aYoung Adult1 aSevilla, T1 aSivera, R1 aMartínez-Rubio, D1 aLupo, V1 aChumillas, M, J1 aCalpena, E1 aDopazo, J1 aVílchez, J, J1 aPalau, F1 aEspinós, C  uhttp://clinbioinfosspa.es/content/egr2-gene-involved-axonal-charcot-marie-tooth-disease02551nas a2200301   4500008004100000022001400041245008500055210006900140260001600209300000700225490000700232520160800239653001501847653001801862653001301880653004201893653001101935653002301946653002701969653001301996100002002009700002002029700002302049700002002072700002002092700002202112856011502134       2015                        eng d  a1471-210500aFast inexact mapping using advanced tree exploration on backward search methods.0 aFast inexact mapping using advanced tree exploration on backward  c2015 Jan 28  a180 v163 a<p><b>BACKGROUND: </b>Short sequence mapping methods for Next Generation Sequencing consist on a combination of seeding techniques followed by local alignment based on dynamic programming approaches. Most seeding algorithms are based on backward search alignment, using the Burrows Wheeler Transform, the Ferragina and Manzini Index or Suffix Arrays. All these backward search algorithms have excellent performance, but their computational cost highly increases when allowing errors. In this paper, we discuss an inexact mapping algorithm based on pruning strategies for search tree exploration over genomic data.</p><p><b>RESULTS: </b>The proposed algorithm achieves a 13x speed-up over similar algorithms when allowing 6 base errors, including insertions, deletions and mismatches. This algorithm can deal with 400 bps reads with up to 9 errors in a high quality Illumina dataset. In this example, the algorithm works as a preprocessor that reduces by 55% the number of reads to be aligned. Depending on the aligner the overall execution time is reduced between 20-40%.</p><p><b>CONCLUSIONS: </b>Although not intended as a complete sequence mapping tool, the proposed algorithm could be used as a preprocessing step to modern sequence mappers. This step significantly reduces the number reads to be aligned, accelerating overall alignment time. Furthermore, this algorithm could be used for accelerating the seeding step of already available sequence mappers. In addition, an out-of-core index has been implemented for working with large genomes on systems without expensive memory configurations.</p>10aAlgorithms10aGenome, Human10aGenomics10aHigh-Throughput Nucleotide Sequencing10aHumans10aSequence Alignment10aSequence Analysis, DNA10aSoftware1 aSalavert, José1 aTomás, Andrés1 aTárraga, Joaquín1 aMedina, Ignacio1 aDopazo, Joaquin1 aBlanquer, Ignacio  uhttp://clinbioinfosspa.es/content/fast-inexact-mapping-using-advanced-tree-exploration-backward-search-methods02385nas a2200397   4500008004100000022001400041245007600055210006900131260001300200300001300213490000700226520116000233653001201393653001801405653002201423653002201445653002301467653002401490653002801514653003801542653001101580653002001591653002801611653001301639653002201652653001401674653003601688653003201724653002401756100002401780700002401804700001801828700002001846700001701866856010401883       2015                        eng d  a1553-735800aA Pan-Cancer Catalogue of Cancer Driver Protein Interaction Interfaces.0 aPanCancer Catalogue of Cancer Driver Protein Interaction Interfa  c2015 Oct  ae10045180 v113 a<p>Despite their importance in maintaining the integrity of all cellular pathways, the role of mutations on protein-protein interaction (PPI) interfaces as cancer drivers has not been systematically studied. Here we analyzed the mutation patterns of the PPI interfaces from 10,028 proteins in a pan-cancer cohort of 5,989 tumors from 23 projects of The Cancer Genome Atlas (TCGA) to find interfaces enriched in somatic missense mutations. To that end we use e-Driver, an algorithm to analyze the mutation distribution of specific protein functional regions. We identified 103 PPI interfaces enriched in somatic cancer mutations. 32 of these interfaces are found in proteins coded by known cancer driver genes. The remaining 71 interfaces are found in proteins that have not been previously identified as cancer drivers even that, in most cases, there is an extensive literature suggesting they play an important role in cancer. Finally, we integrate these findings with clinical information to show how tumors apparently driven by the same gene have different behaviors, including patient outcomes, depending on which specific interfaces are mutated. </p>10aAnimals10aBase Sequence10aBiomarkers, Tumor10aCatalogs as Topic10aChromosome Mapping10aComputer Simulation10aDNA Mutational Analysis10aGenetic Predisposition to Disease10aHumans10aModels, Genetic10aMolecular Sequence Data10amutation10aNeoplasm Proteins10aNeoplasms10aPolymorphism, Single Nucleotide10aProtein Interaction Mapping10aSignal Transduction1 aPorta-Pardo, Eduard1 aGarcía-Alonso, Luz1 aHrabe, Thomas1 aDopazo, Joaquin1 aGodzik, Adam  uhttp://clinbioinfosspa.es/content/pan-cancer-catalogue-cancer-driver-protein-interaction-interfaces02531nas a2200361   4500008004100000022001400041245008000055210006900135260001300204300001300217490000800230520137100238653001801609653004901627653003401676653001701710653001101727653002801738653002301766653001301789653002501802653002701827653001001854100003301864700002301897700002801920700003301948700002201981700002002003700001902023700002502042856010202067       2015                        eng d  a1552-483300aRe-evaluation casts doubt on the pathogenicity of homozygous USH2A p.C759F.0 aReevaluation casts doubt on the pathogenicity of homozygous USH2  c2015 Jul  a1597-6000 v1673 a<p>Mutations in USH2A are a common cause of Retinitis Pigmentosa (RP). Among the most frequently reported USH2A variants, c.2276G>T (p.C759F) has been found in both affected and healthy individuals. The pathogenicity of this variant remains controversial since it was detected in homozygosity in two healthy siblings of a Spanish family (S23), eleven years ago. The fact that these individuals remain asymptomatic today, prompted us to study the presence of other pathogenic variants in this family using targeted resequencing of 26 retinal genes in one of the affected individuals. This approach allowed us to identify one novel pathogenic homozygous mutation in exon 13 of PDE6B (c.1678C>T; p.R560C). This variant cosegregated with the disease and was absent in 200 control individuals. Remarkably, the identified variant in PDE6B corresponds to the mutation responsible of the retinal degeneration in the naturally occurring rd10 mutant mice. To our knowledge, this is the first report of the identification of the rd10 mice mutation in a RP family. These findings, together with a review of the literature, support the hypothesis that homozygous p.C759F mutations are not pathogenic and led us to exclude the implication of p.C759F in the RP of family S23. Our results indicate the need of re-evaluating all families genetically diagnosed with this mutation.</p>10aBase Sequence10aCyclic Nucleotide Phosphodiesterases, Type 610aExtracellular Matrix Proteins10aGene Library10aHumans10aMolecular Sequence Data10aMutation, Missense10aPedigree10aRetinitis pigmentosa10aSequence Analysis, DNA10aSpain1 aDel Pozo, María, González-1 aBravo-Gil, Nereida1 aMéndez-Vidal, Cristina1 aMontero-de-Espinosa, Ignacio1 aMillán, José, M1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo  uhttp://clinbioinfosspa.es/content/re-evaluation-casts-doubt-pathogenicity-homozygous-ush2a-pc759f01866nas a2200337   4500008004100000022001400041245010900055210006900164260001600233300001000249490000600259520081400265653001501079653002601094653001501120653002101135653001801156653002001174653001101194653001901205653001401224653002001238653001301258653002401271100001901295700003001314700001901344700002401363700002001387856012101407       2015                        eng d  a2045-232200aUsing activation status of signaling pathways as mechanism-based biomarkers to predict drug sensitivity.0 aUsing activation status of signaling pathways as mechanismbased   c2015 Dec 18  a184940 v53 a<p>Many complex traits, as drug response, are associated with changes in biological pathways rather than being caused by single gene alterations. Here, a predictive framework is presented in which gene expression data are recoded into activity statuses of signal transduction circuits (sub-pathways within signaling pathways that connect receptor proteins to final effector proteins that trigger cell actions). Such activity values are used as features by a prediction algorithm which can efficiently predict a continuous variable such as the IC50 value. The main advantage of this prediction method is that the features selected by the predictor, the signaling circuits, are themselves rich-informative, mechanism-based biomarkers which provide insight into or drug molecular mechanisms of action (MoA). </p>10aAlgorithms10aAntineoplastic Agents10abiomarkers10aCell Line, Tumor10aCell Survival10agene expression10aHumans10aLethal Dose 5010aNeoplasms10aPhosphorylation10aProteins10aSignal Transduction1 aAmadoz, Alicia1 aSebastián-Leon, Patricia1 aVidal, Enrique1 aSalavert, Francisco1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/using-activation-status-signaling-pathways-mechanism-based-biomarkers-predict-drug03593nas a2200601   4500008004100000022001400041245013900055210006900194260001600263300001200279490000700291520163400298653002401932653001201956653002501968653002301993653001402016653002502030653001002055653003402065653004202099653001502141653001102156653002802167653002002195653001302215653001102228653003702239653003602276653002502312653002602337100003002363700002402393700001802417700003202435700002002467700002302487700002902510700002202539700003402561700002602595700003302621700002802654700002702682700001802709700002902727700002002756700002802776700002102804700002002825700001802845856012802863       2015                        eng d  a1460-208300aWhole-exome sequencing reveals ZNF408 as a new gene associated with autosomal recessive retinitis pigmentosa with vitreal alterations.0 aWholeexome sequencing reveals ZNF408 as a new gene associated wi  c2015 Jul 15  a4037-480 v243 a<p>Retinitis pigmentosa (RP) is a group of progressive inherited retinal dystrophies that cause visual impairment as a result of photoreceptor cell death. RP is heterogeneous, both clinically and genetically making difficult to establish precise genotype-phenotype correlations. In a Spanish family with autosomal recessive RP (arRP), homozygosity mapping and whole-exome sequencing led to the identification of a homozygous mutation (c.358_359delGT; p.Ala122Leufs*2) in the ZNF408 gene. A screening performed in 217 additional unrelated families revealed another homozygous mutation (c.1621C>T; p.Arg541Cys) in an isolated RP case. ZNF408 encodes a transcription factor that harbors 10 predicted C2H2-type fingers thought to be implicated in DNA binding. To elucidate the ZNF408 role in the retina and the pathogenesis of these mutations we have performed different functional studies. By immunohistochemical analysis in healthy human retina, we identified that ZNF408 is expressed in both cone and rod photoreceptors, in a specific type of amacrine and ganglion cells, and in retinal blood vessels. ZNF408 revealed a cytoplasmic localization and a nuclear distribution in areas corresponding with the euchromatin fraction. Immunolocalization studies showed a partial mislocalization of the p.Arg541Cys mutant protein retaining part of the WT protein in the cytoplasm. Our study demonstrates that ZNF408, previously associated with Familial Exudative Vitreoretinopathy (FEVR), is a new gene causing arRP with vitreous condensations supporting the evidence that this protein plays additional functions into the human retina. </p>10aAmino Acid Sequence10aAnimals10aChlorocebus aethiops10aChromosome Mapping10aCOS Cells10aDNA-Binding Proteins10aExome10aGenome-Wide Association Study10aHigh-Throughput Nucleotide Sequencing10aHomozygote10aHumans10aMolecular Sequence Data10aMutant Proteins10aPedigree10aRetina10aRetinal Cone Photoreceptor Cells10aRetinal Rod Photoreceptor Cells10aRetinitis pigmentosa10aTranscription Factors1 aAvila-Fernandez, Almudena1 aPerez-Carro, Raquel1 aCorton, Marta1 aLopez-Molina, Maria, Isabel1 aCampello, Laura1 aGaranto, Alejandro1 aFernandez-Sanchez, Laura1 aDuijkers, Lonneke1 aLopez-Martinez, Miguel, Angel1 aRiveiro-Alvarez, Rosa1 ada Silva, Luciana, Rodrigues1 aSanchez-Alcudia, Rocío1 aMartin-Garrido, Esther1 aReyes, Noelia1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aGarcia-Sandoval, Blanca1 aCollin, Rob, W J1 aCuenca, Nicolas1 aAyuso, Carmen  uhttp://clinbioinfosspa.es/content/whole-exome-sequencing-reveals-znf408-new-gene-associated-autosomal-recessive-retinitis-002775nas a2200445   4500008004100000022001400041245012000055210006900175260000900244300001200253490000600265520144600271653001501717653001001732653002401742653001801766653001001784653002701794653002801821653001001849653001101859653001101870653001101881653002501892653000901917653001601926653002801942653001301970653001301983653002401996653001402020100003302034700002802067700002302095700002202118700002002140700001902160700002502179856012502204       2014                        eng d  a1932-620300aExome sequencing reveals novel and recurrent mutations with clinical significance in inherited retinal dystrophies.0 aExome sequencing reveals novel and recurrent mutations with clin  c2014  ae1161760 v93 a<p>This study aimed to identify the underlying molecular genetic cause in four Spanish families clinically diagnosed of Retinitis Pigmentosa (RP), comprising one autosomal dominant RP (adRP), two autosomal recessive RP (arRP) and one with two possible modes of inheritance: arRP or X-Linked RP (XLRP). We performed whole exome sequencing (WES) using NimbleGen SeqCap EZ Exome V3 sample preparation kit and SOLID 5500xl platform. All variants passing filter criteria were validated by Sanger sequencing to confirm familial segregation and the absence in local control population. This strategy allowed the detection of: (i) one novel heterozygous splice-site deletion in RHO, c.937-2_944del, (ii) one rare homozygous mutation in C2orf71, c.1795T>C; p.Cys599Arg, not previously associated with the disease, (iii) two heterozygous null mutations in ABCA4, c.2041C>T; p.R681* and c.6088C>T; p.R2030*, and (iv) one mutation, c.2405-2406delAG; p.Glu802Glyfs*31 in the ORF15 of RPGR. The molecular findings for RHO and C2orf71 confirmed the initial diagnosis of adRP and arRP, respectively, while patients with the two ABCA4 mutations, both previously associated with Stargardt disease, presented symptoms of RP with early macular involvement. Finally, the X-Linked inheritance was confirmed for the family with the RPGR mutation. This latter finding allowed the inclusion of carrier sisters in our preimplantational genetic diagnosis program. </p>10aAdolescent10aAdult10aAmino Acid Sequence10aBase Sequence10aChild10aChromosome Segregation10aDNA Mutational Analysis10aExome10aFamily10aFemale10aHumans10aInheritance Patterns10aMale10aMiddle Aged10aMolecular Sequence Data10amutation10aPedigree10aRetinal Dystrophies10aRhodopsin1 adel Pozo, María, González-1 aMéndez-Vidal, Cristina1 aBravo-Gil, Nereida1 aVela-Boza, Alicia1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo  uhttp://clinbioinfosspa.es/content/exome-sequencing-reveals-novel-and-recurrent-mutations-clinical-significance-inherited01909nas a2200265   4500008004100000022001400041245007900055210006900134260001600203300001100219490000700230520106400237653001001301653001801311653004201329653001101371653002701382653001301409100003301422700002301455700001901478700002001497700002701517856009901544       2014                        eng d  a1367-481100angsCAT: a tool to assess the efficiency of targeted enrichment sequencing.0 angsCAT a tool to assess the efficiency of targeted enrichment se  c2014 Jun 15  a1767-80 v303 a<p><b>MOTIVATION: </b>Targeted enrichment sequencing by next-generation sequencing is a common approach to interrogate specific loci or the whole exome in the human genome. The efficiency and the lack of bias in the enrichment process need to be assessed as a quality control step before performing downstream analysis of the sequence data. Tools that can report on the sensitivity, specificity, uniformity and other enrichment-specific features are needed.</p><p><b>RESULTS: </b>We have implemented the next-generation sequencing data Capture Assessment Tool (ngsCAT), a tool that takes the information of the mapped reads and the coordinates of the targeted regions as input files, and generates a report with metrics and figures that allows the evaluation of the efficiency of the enrichment process. The tool can also take as input the information of two samples allowing the comparison of two different experiments.</p><p><b>AVAILABILITY AND IMPLEMENTATION: </b>Documentation and downloads for ngsCAT can be found at http://www.bioinfomgp.org/ngscat.</p>10aExome10aGenome, Human10aHigh-Throughput Nucleotide Sequencing10aHumans10aSequence Analysis, DNA10aSoftware1 aLópez-Domingo, Francisco, J1 aFlorido, Javier, P1 aRueda, Antonio1 aDopazo, Joaquin1 aSantoyo-López, Javier  uhttp://clinbioinfosspa.es/content/ngscat-tool-assess-efficiency-targeted-enrichment-sequencing03760nas a2200397   4500008004100000022001400041245013500055210006900190260001600259300000800275490000700283520244800290653002602738653001802764653002502782653002802807653001702835653002102852653003202873653001102905653002702916653003602943653002302979653001303002653001403015653001103029653002503040100002803065700002303093700003303116700002203149700002003171700001903191700002503210856012703235       2014                        eng d  a1471-215600aNovel RP1 mutations and a recurrent BBS1 variant explain the co-existence of two distinct retinal phenotypes in the same pedigree.0 aNovel RP1 mutations and a recurrent BBS1 variant explain the coe  c2014 Dec 14  a1430 v153 a<p><b>BACKGROUND: </b>Molecular diagnosis of Inherited Retinal Dystrophies (IRD) has long been challenging due to the extensive clinical and genetic heterogeneity present in this group of disorders. Here, we describe the clinical application of an integrated next-generation sequencing approach to determine the underlying genetic defects in a Spanish family with a provisional clinical diagnosis of autosomal recessive Retinitis Pigmentosa (arRP).</p><p><b>RESULTS: </b>Exome sequencing of the index patient resulted in the identification of the homozygous BBS1 p.M390R mutation. Sanger sequencing of additional members of the family showed lack of co-segregation of the p.M390R variant in some individuals. Clinical reanalysis indicated co-ocurrence of two different phenotypes in the same family: Bardet-Biedl syndrome in the individual harboring the BBS1 mutation and non-syndromic arRP in extended family members. To identify possible causative mutations underlying arRP, we conducted disease-targeted gene sequencing using a panel of 26 IRD genes. The in-house custom panel was validated using 18 DNA samples known to harbor mutations in relevant genes. All variants were redetected, indicating a high mutation detection rate. This approach allowed the identification of two novel heterozygous null mutations in RP1 (c.4582_4585delATCA; p.I1528Vfs*10 and c.5962dupA; p.I1988Nfs*3) which co-segregated with the disease in arRP patients. Additionally, a mutational screening in 96 patients of our cohort with genetically unresolved IRD revealed the presence of the c.5962dupA mutation in one unrelated family.</p><p><b>CONCLUSIONS: </b>The combination of molecular findings for RP1 and BBS1 genes through exome and gene panel sequencing enabled us to explain the co-existence of two different retinal phenotypes in a family. The identification of two novel variants in RP1 suggests that the use of panels containing the prevalent genes of a particular population, together with an optimized data analysis pipeline, is an efficient and cost-effective approach that can be reliably implemented into the routine diagnostic process of diverse inherited retinal disorders. Moreover, the identification of these novel variants in two unrelated families supports the relatively high prevalence of RP1 mutations in Spanish population and the role of private mutations for commonly mutated genes, while extending the mutational spectrum of RP1.</p>10aBardet-Biedl Syndrome10aBase Sequence10aCase-Control Studies10aDNA Mutational Analysis10aEye Proteins10aGenes, Recessive10aGenetic Association Studies10aHumans10aMicrosatellite Repeats10aMicrotubule-Associated Proteins10aMutation, Missense10aPedigree10aPhenotype10aRetina10aRetinitis pigmentosa1 aMéndez-Vidal, Cristina1 aBravo-Gil, Nereida1 adel Pozo, María, González-1 aVela-Boza, Alicia1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo  uhttp://clinbioinfosspa.es/content/novel-rp1-mutations-and-recurrent-bbs1-variant-explain-co-existence-two-distinct-retinal02932nas a2200397   4500008004100000022001400041245010000055210006900155260001600224300000800240490000700248520172500255653001201980653001001992653001702002653002202019653002502041653001802066653001302084653001102097653002002108653001302128653001402141653002502155653002902180653002702209653001102236100002402247700002902271700003102300700002202331700002702353700002502380700002002405856010902425       2014                        eng d  a1744-429200aThe role of the interactome in the maintenance of deleterious variability in human populations.0 arole of the interactome in the maintenance of deleterious variab  c2014 Sep 26  a7520 v103 a<p>Recent genomic projects have revealed the existence of an unexpectedly large amount of deleterious variability in the human genome. Several hypotheses have been proposed to explain such an apparently high mutational load. However, the mechanisms by which deleterious mutations in some genes cause a pathological effect but are apparently innocuous in other genes remain largely unknown. This study searched for deleterious variants in the 1,000 genomes populations, as well as in a newly sequenced population of 252 healthy Spanish individuals. In addition, variants causative of monogenic diseases and somatic variants from 41 chronic lymphocytic leukaemia patients were analysed. The deleterious variants found were analysed in the context of the interactome to understand the role of network topology in the maintenance of the observed mutational load. Our results suggest that one of the mechanisms whereby the effect of these deleterious variants on the phenotype is suppressed could be related to the configuration of the protein interaction network. Most of the deleterious variants observed in healthy individuals are concentrated in peripheral regions of the interactome, in combinations that preserve their connectivity, and have a marginal effect on interactome integrity. On the contrary, likely pathogenic cancer somatic deleterious variants tend to occur in internal regions of the interactome, often with associated structural consequences. Finally, variants causative of monogenic diseases seem to occupy an intermediate position. Our observations suggest that the real pathological potential of a variant might be more a systems property rather than an intrinsic property of individual proteins. </p>10aAlleles10aExome10aGene Library10aGenetic Variation10aGenetics, Population10aGenome, Human10aGenomics10aHumans10aModels, Genetic10amutation10aPhenotype10aProtein Conformation10aProtein Interaction Maps10aSequence Analysis, DNA10aWhites1 aGarcía-Alonso, Luz1 aJiménez-Almazán, Jorge1 aCarbonell-Caballero, José1 aVela-Boza, Alicia1 aSantoyo-López, Javier1 aAntiňolo, Guillermo1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/role-interactome-maintenance-deleterious-variability-human-populations03195nas a2200517   4500008004100000022001400041245017300055210006900228260001300297300001000310490000700320520152000327653003201847653003101879653001601910653001101926653000901937653002301946653002801969653001501997653002002012100002802032700002302060700001602083700002402099700002502123700002102148700001902169700002202188700002102210700002002231700002002251700002202271700001902293700002102312700002802333700002202361700002002383700001702403700002702420700002602447700002102473700002402494700002802518856013102546       2014                        eng d  a1098-100400aTwo novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients.0 aTwo novel mutations in the BCKDK branchedchain ketoacid dehydrog  c2014 Apr  a470-70 v353 a<p>Inactivating mutations in the BCKDK gene, which codes for the kinase responsible for the negative regulation of the branched-chain α-keto acid dehydrogenase complex (BCKD), have recently been associated with a form of autism in three families. In this work, two novel exonic BCKDK mutations, c.520C>G/p.R174G and c.1166T>C/p.L389P, were identified at the homozygous state in two unrelated children with persistently reduced body fluid levels of branched-chain amino acids (BCAAs), developmental delay, microcephaly, and neurobehavioral abnormalities. Functional analysis of the mutations confirmed the missense character of the c.1166T>C change and showed a splicing defect r.[520c>g;521_543del]/p.R174Gfs1*, for c.520C>G due to the presence of a new donor splice site. Mutation p.L389P showed total loss of kinase activity. Moreover, patient-derived fibroblasts showed undetectable (p.R174Gfs1*) or barely detectable (p.L389P) levels of BCKDK protein and its phosphorylated substrate (phospho-E1α), resulting in increased BCKD activity and the very rapid BCAA catabolism manifested by the patients' clinical phenotype. Based on these results, a protein-rich diet plus oral BCAA supplementation was implemented in the patient homozygous for p.R174Gfs1*. This treatment normalized plasma BCAA levels and improved growth, developmental and behavioral variables. Our results demonstrate that BCKDK mutations can result in neurobehavioral deficits in humans and support the rationale for dietary intervention. </p>10aAmino Acids, Branched-Chain10aDevelopmental Disabilities10aFibroblasts10aHumans10aMale10aMutation, Missense10aNervous System Diseases10aPediatrics10aProtein Kinases1 aGarcía-Cazorla, Angels1 aOyarzabal, Alfonso1 aFort, Joana1 aRobles, Concepción1 aCastejón, Esperanza1 aRuiz-Sala, Pedro1 aBodoy, Susanna1 aMerinero, Begoña1 aLopez-Sala, Anna1 aDopazo, Joaquin1 aNunes, Virginia1 aUgarte, Magdalena1 aArtuch, Rafael1 aPalacín, Manuel1 aRodríguez-Pombo, Pilar1 aAlcaide, Patricia1 aNavarrete, Rosa1 aSanz, Paloma1 aFont-Llitjós, Mariona1 aVilaseca, Ma, Antonia1 aOrmaizabal, Aida1 aPristoupilova, Anna1 aAgulló, Sergi, Beltran  uhttp://clinbioinfosspa.es/content/two-novel-mutations-bckdk-branched-chain-keto-acid-dehydrogenase-kinase-gene-are-responsible02637nas a2200397   4500008004100000022001400041245009900055210006900154260000900223300001100232490000600243520136900249653003101618653001601649653002501665653002601690653002501716653003001741653002901771653001801800653001101818653003401829653002701863653002601890100001801916700002601934700002401960700002001984700001702004700001902021700002002040700002002060700001602080700001802096856012502114       2013                        eng d  a1932-620300aDefining the genomic signature of totipotency and pluripotency during early human development.0 aDefining the genomic signature of totipotency and pluripotency d  c2013  ae621350 v83 a<p>The genetic mechanisms governing human pre-implantation embryo development and the in vitro counterparts, human embryonic stem cells (hESCs), still remain incomplete. Previous global genome studies demonstrated that totipotent blastomeres from day-3 human embryos and pluripotent inner cell masses (ICMs) from blastocysts, display unique and differing transcriptomes. Nevertheless, comparative gene expression analysis has revealed that no significant differences exist between hESCs derived from blastomeres versus those obtained from ICMs, suggesting that pluripotent hESCs involve a new developmental progression. To understand early human stages evolution, we developed an undifferentiation network signature (UNS) and applied it to a differential gene expression profile between single blastomeres from day-3 embryos, ICMs and hESCs. This allowed us to establish a unique signature composed of highly interconnected genes characteristic of totipotency (61 genes), in vivo pluripotency (20 genes), and in vitro pluripotency (107 genes), and which are also proprietary according to functional analysis. This systems biology approach has led to an improved understanding of the molecular and signaling processes governing human pre-implantation embryo development, as well as enabling us to comprehend how hESCs might adapt to in vitro culture conditions.</p>10aBlastocyst Inner Cell Mass10aBlastomeres10aCell Differentiation10aEmbryonic Development10aEmbryonic Stem Cells10aGene Expression Profiling10aGene Regulatory Networks10aGenome, Human10aHumans10aMolecular Sequence Annotation10aPluripotent Stem Cells10aTotipotent Stem Cells1 aGalan, Amparo1 aDiaz-Gimeno, Patricia1 aPoo, Maria, Eugenia1 aValbuena, Diana1 aSanchez, Eva1 aRuiz, Veronica1 aDopazo, Joaquin1 aMontaner, David1 aConesa, Ana1 aSimon, Carlos  uhttp://clinbioinfosspa.es/content/defining-genomic-signature-totipotency-and-pluripotency-during-early-human-development02838nas a2200349   4500008004100000022001400041245010300055210006900158260001700227300001100244490000700255520180200262653001002064653001102074653003002085653001102115653000902126653001602135653000902151653003302160653003302193100001502226700001502241700001602256700001202272700001502284700001602299700001402315700001302329700001502342856013102357       2013                        eng d  a0393-974X00aDifferential gene-expression analysis defines a molecular pattern related to olive pollen allergy.0 aDifferential geneexpression analysis defines a molecular pattern  c2013 Apr-Jun  a337-500 v273 a<p>Analysis of gene-expression profiles by microarrays is useful for characterization of candidate genes, key regulatory networks, and to define phenotypes or molecular signatures which improve the diagnosis and/or classification of the allergic processes. We have used this approach in the study of olive pollen response in order to find differential molecular markers among responders and non-responders to this allergenic source. Five clinical groups, non-allergic, asymptomatic, allergic but not to olive pollen, untreated-olive-pollen allergic patients and olive-pollen allergic patients (under specific-immunotherapy), were assessed during and outside pollen seasons. Whole-genome gene expression analysis was performed in RNAs extracted from PBMCs. After assessment of data quality and principal components analysis (PCA), differential gene-expression, by multiple testing and, functional analyses by KEGG, for pathways and Gene-Ontology for biological processes were performed. Relevance was defined by fold change and corrected P values (less than 0.05). The most differential genes were validated by qRT-PCR in a larger set of individuals. Interestingly, gene-expression profiling obtained by PCA clearly showed five clusters of samples that correlated with the five clinical groups. Furthermore, differential gene expression and functional analyses revealed differential genes and pathways in the five clinical groups. The 93 most significant genes found were validated, and one set of 35 genes was able to discriminate profiles of olive pollen response. Our results, in addition to providing new information on allergic response, define a possible molecular signature for olive pollen allergy which could be useful for the diagnosis and treatment of this and other sensitizations. </p>10aAdult10aFemale10aGene Expression Profiling10aHumans10aMale10aMiddle Aged10aOlea10aPrincipal Component Analysis10aRhinitis, Allergic, Seasonal1 aAguerri, M1 aCalzada, D1 aMontaner, D1 aMata, M1 aFlorido, F1 aQuiralte, J1 aDopazo, J1 aLahoz, C1 aCardaba, B  uhttp://clinbioinfosspa.es/content/differential-gene-expression-analysis-defines-molecular-pattern-related-olive-pollen-allergy02655nas a2200421   4500008004100000022001400041245010400055210006900159260001700228300000900245490000800254520136600262653001501628653001001643653003201653653001001685653001001695653001101705653004201716653001101758653001101769653000901780653003001789653001301819100001901832700003401851700002701885700002601912700002801938700002301966700001901989700002902008700002002037700001702057700001802074700001902092856012202111       2013                        eng d  a1096-720600aExome sequencing identifies a new mutation in SERAC1 in a patient with 3-methylglutaconic aciduria.0 aExome sequencing identifies a new mutation in SERAC1 in a patien  c2013 Sep-Oct  a73-70 v1103 a<p>3-Methylglutaconic aciduria (3-MGA-uria) is a heterogeneous group of syndromes characterized by an increased excretion of 3-methylglutaconic and 3-methylglutaric acids. Five types of 3-MGA-uria (I to V) with different clinical presentations have been described. Causative mutations in TAZ, OPA3, DNAJC19, ATP12, ATP5E, and TMEM70 have been identified. After excluding the known genetic causes of 3-MGA-uria we used exome sequencing to investigate a patient with Leigh syndrome and 3-MGA-uria. We identified a homozygous variant in SERAC1 (c.202C>T; p.Arg68*), that generates a premature stop codon at position 68 of SERAC1 protein. Western blot analysis in patient's fibroblasts showed a complete absence of SERAC1 that was consistent with the prediction of a truncated protein and supports the pathogenic role of the mutation. During the course of this project a parallel study identified mutations in SERAC1 as the genetic cause of the disease in 15 patients with MEGDEL syndrome, which was compatible with the clinical and biochemical phenotypes of the patient described here. In addition, our patient developed microcephaly and optic atrophy, two features not previously reported in MEGDEL syndrome. We highlight the usefulness of exome sequencing to reveal the genetic bases of human rare diseases even if only one affected individual is available. </p>10aAdolescent10aAdult10aCarboxylic Ester Hydrolases10aChild10aExome10aFemale10aHigh-Throughput Nucleotide Sequencing10aHumans10aInfant10aMale10aMetabolism, Inborn Errors10amutation1 aTort, Frederic1 aGarcía-Silva, María, Teresa1 aFerrer-Cortès, Xènia1 aNavarro-Sastre, Aleix1 aGarcia-Villoria, Judith1 aColl, Maria, Josep1 aVidal, Enrique1 aJiménez-Almazán, Jorge1 aDopazo, Joaquin1 aBriones, Paz1 aElpeleg, Orly1 aRibes, Antonia  uhttp://clinbioinfosspa.es/content/exome-sequencing-identifies-new-mutation-serac1-patient-3-methylglutaconic-aciduria02226nas a2200313   4500008004100000022001400041245008600055210006900141260001300210300001100223490000700234520127400241653001201515653001101527653001301538653000901551653002401560653002801584653002401612653001301636653001801649100003001667700002101697700002401718700002101742700002001763700002001783856010901803       2013                        eng d  a1362-496200aInferring the functional effect of gene expression changes in signaling pathways.0 aInferring the functional effect of gene expression changes in si  c2013 Jul  aW213-70 v413 a<p>Signaling pathways constitute a valuable source of information that allows interpreting the way in which alterations in gene activities affect to particular cell functionalities. There are web tools available that allow viewing and editing pathways, as well as representing experimental data on them. However, few methods aimed to identify the signaling circuits, within a pathway, associated to the biological problem studied exist and none of them provide a convenient graphical web interface. We present PATHiWAYS, a web-based signaling pathway visualization system that infers changes in signaling that affect cell functionality from the measurements of gene expression values in typical expression microarray case-control experiments. A simple probabilistic model of the pathway is used to estimate the probabilities for signal transmission from any receptor to any final effector molecule (taking into account the pathway topology) using for this the individual probabilities of gene product presence/absence inferred from gene expression values. Significant changes in these probabilities allow linking different cell functionalities triggered by the pathway to the biological problem studied. PATHiWAYS is available at: http://pathiways.babelomics.org/. </p>10aAnimals10aHumans10aInternet10aMice10aModels, Statistical10aReceptors, Cell Surface10aSignal Transduction10aSoftware10aTranscriptome1 aSebastián-Leon, Patricia1 aCarbonell, José1 aSalavert, Francisco1 aSánchez, Rubén1 aMedina, Ignacio1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/inferring-functional-effect-gene-expression-changes-signaling-pathways02926nas a2200445   4500008004100000022001400041245009600055210006900151260000900220300001100229490000600240520152900246653002101775653001401796653002101810653002301831653002101854653001101875653002001886653003001906653004301936653003001979653001102009653001602020653002602036653002402062653002602086100002702112700002102139700002902160700001602189700003002205700002002235700001702255700001802272700002402290700002002314700002102334856012502355       2013                        eng d  a1932-620300aMammosphere formation in breast carcinoma cell lines depends upon expression of E-cadherin.0 aMammosphere formation in breast carcinoma cell lines depends upo  c2013  ae772810 v83 a<p>Tumors are heterogeneous at the cellular level where the ability to maintain tumor growth resides in discrete cell populations. Floating sphere-forming assays are broadly used to test stem cell activity in tissues, tumors and cell lines. Spheroids are originated from a small population of cells with stem cell features able to grow in suspension culture and behaving as tumorigenic in mice. We tested the ability of eleven common breast cancer cell lines representing the major breast cancer subtypes to grow as mammospheres, measuring the ability to maintain cell viability upon serial non-adherent passage. Only MCF7, T47D, BT474, MDA-MB-436 and JIMT1 were successfully propagated as long-term mammosphere cultures, measured as the increase in the number of viable cells upon serial non-adherent passages. Other cell lines tested (SKBR3, MDA-MB-231, MDA-MB-468 and MDA-MB-435) formed cell clumps that can be disaggregated mechanically, but cell viability drops dramatically on their second passage. HCC1937 and HCC1569 cells formed typical mammospheres, although they could not be propagated as long-term mammosphere cultures. All the sphere forming lines but MDA-MB-436 express E-cadherin on their surface. Knock down of E-cadherin expression in MCF-7 cells abrogated its ability to grow as mammospheres, while re-expression of E-cadherin in SKBR3 cells allow them to form mammospheres. Therefore, the mammosphere assay is suitable to reveal stem like features in breast cancer cell lines that express E-cadherin.</p>10aBreast Neoplasms10aCadherins10aCell Line, Tumor10aCell Proliferation10aCluster Analysis10aFemale10agene expression10aGene Expression Profiling10aGene Expression Regulation, Neoplastic10aGene Knockdown Techniques10aHumans10aMCF-7 Cells10aNeoplastic Stem Cells10aSpheroids, Cellular10aTumor Cells, Cultured1 aIglesias, Juan, Manuel1 aBeloqui, Izaskun1 aGarcia-Garcia, Francisco1 aLeis, Olatz1 aVazquez-Martin, Alejandro1 aEguiara, Arrate1 aCufi, Silvia1 aPavon, Andres1 aMenendez, Javier, A1 aDopazo, Joaquin1 aMartin, Angel, G  uhttp://clinbioinfosspa.es/content/mammosphere-formation-breast-carcinoma-cell-lines-depends-upon-expression-e-cadherin-002952nas a2200481   4500008004100000022001400041245013400055210006900189260001600258300001100274490000800285520141700293653002801710653002501738653001001763653001501773653001601788653002001804653002001824653003001844653001101874653000901885653001601894653004401910653001901954653001801973100002401991700002402015700002602039700002502065700002402090700002202114700001802136700002002154700002902174700002902203700001802232700002402250700002402274700002502298700002102323856012602344       2013                        eng d  a1873-349200aNovel genes detected by transcriptional profiling from whole-blood cells in patients with early onset of acute coronary syndrome.0 aNovel genes detected by transcriptional profiling from wholebloo  c2013 Jun 05  a184-900 v4213 a<p><b>BACKGROUND: </b>Genome-wide expression analysis using microarrays has been used as a research strategy to discovery new biomarkers and candidate genes for a number of diseases. We aim to find new biomarkers for the prediction of acute coronary syndrome (ACS) with a differentially expressed mRNA profiling approach using whole genomic expression analysis in a peripheral blood cell model from patients with early ACS.</p><p><b>METHODS AND RESULTS: </b>This study was carried out in two phases. On phase 1 a restricted clinical criteria (ACS-Ph1, n=9 and CG-Ph1, n=6) was used in order to select potential mRNA biomarkers candidates. A subsequent phase 2 study was performed using selected phase 1 markers analyzed by RT-qPCR using a larger and independent casuistic (ACS-Ph2, n=74 and CG-Ph2, n=41). A total of 549 genes were found to be differentially expressed in the first 48 h after the ACS-Ph1. Technical and biological validation further confirmed that ALOX15, AREG, BCL2A1, BCL2L1, CA1, COX7B, ECHDC3, IL18R1, IRS2, KCNE1, MMP9, MYL4 and TREML4, are differentially expressed in both phases of this study.</p><p><b>CONCLUSIONS: </b>Transcriptomic analysis by microarray technology demonstrated differential expression during a 48 h time course suggesting a potential use of some of these genes as biomarkers for very early stages of ACS, as well as for monitoring early cardiac ischemic recovery.</p>10aAcute Coronary Syndrome10aAcute-Phase Proteins10aAdult10abiomarkers10aBlood Cells10aEarly Diagnosis10agene expression10aGene Expression Profiling10aHumans10aMale10aMiddle Aged10aOligonucleotide Array Sequence Analysis10aRNA, Messenger10aTranscriptome1 aSilbiger, Vivian, N1 aLuchessi, André, D1 aHirata, Rosário, D C1 aLima-Neto, Lídio, G1 aCavichioli, Débora1 aCarracedo, Ángel1 aBrión, Maria1 aDopazo, Joaquin1 aGarcia-Garcia, Francisco1 aSantos, Elizabete, S Dos1 aRamos, Rui, F1 aSampaio, Marcelo, F1 aArmaganijan, Dikran1 aSousa, Amanda, G M R1 aHirata, Mario, H  uhttp://clinbioinfosspa.es/content/novel-genes-detected-transcriptional-profiling-whole-blood-cells-patients-early-onset-002672nas a2200409   4500008004100000022001400041245006600055210006400121260001600185300000800201490000600209520145600215653001101671653003801682653001301720653002501733653001101758653000901769653003601778100002601814700001701840700002301857700002401880700001901904700002201923700002001945700002401965700001601989700002502005700002302030700002402053700002602077700002502103700002002128700001902148856009502167       2013                        eng d  a1750-117200aPathways systematically associated to Hirschsprung's disease.0 aPathways systematically associated to Hirschsprungs disease  c2013 Dec 02  a1870 v83 a<p>Despite it has been reported that several loci are involved in Hirschsprung's disease, the molecular basis of the disease remains yet essentially unknown. The study of collective properties of modules of functionally-related genes provides an efficient and sensitive statistical framework that can overcome sample size limitations in the study of rare diseases. Here, we present the extension of a previous study of a Spanish series of HSCR trios to an international cohort of 162 HSCR trios to validate the generality of the underlying functional basis of the Hirschsprung's disease mechanisms previously found. The Pathway-Based Analysis (PBA) confirms a strong association of gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other processes related to the disease. In addition, network analysis recovers sub-networks significantly associated to the disease, which contain genes related to the same functionalities, thus providing an independent validation of these findings. The functional profiles of association obtained for patients populations from different countries were compared to each other. While gene associations were different at each series, the main functional associations were identical in all the five populations. These observations would also explain the reported low reproducibility of associations of individual disease genes across populations. </p>10aFemale10aGenetic Predisposition to Disease10aGenotype10aHirschsprung Disease10aHumans10aMale10aPolymorphism, Single Nucleotide1 aFernández, Raquel, M1 aBleda, Marta1 aLuzón-Toro, Berta1 aGarcía-Alonso, Luz1 aArnold, Stacey1 aSribudiani, Yunia1 aBesmond, Claude1 aLantieri, Francesca1 aDoan, Betty1 aCeccherini, Isabella1 aLyonnet, Stanislas1 aHofstra, Robert, Mw1 aChakravarti, Aravinda1 aAntiňolo, Guillermo1 aDopazo, Joaquin1 aBorrego, Salud  uhttp://clinbioinfosspa.es/content/pathways-systematically-associated-hirschsprungs-disease02722nas a2200505   4500008004100000022001400041245018900055210006900244260001300313300001000326490000700336520107200343653002801415653001001443653000901453653002201462653001101484653003801495653001101533653003001544653004401574653004301618653001601661653001101677653001701688653005001705653001401755653000901769653001601778653002001794653001401814653003201828653002801860653000901888653001901897653002101916100003001937700001901967700002001986700002002006700002902026700002002055700001702075856012402092       2013                        eng d  a1600-062500aRole of CPI-17 in restoring skin homoeostasis in cutaneous field of cancerization: effects of topical application of a film-forming medical device containing photolyase and UV filters.0 aRole of CPI17 in restoring skin homoeostasis in cutaneous field   c2013 Jul  a494-60 v223 a<p>Cutaneous field of cancerization (CFC) is caused in part by the carcinogenic effect of the cyclobutane pyrimidine dimers CPD and 6-4 photoproducts (6-4PPs). Photoreactivation is carried out by photolyases which specifically recognize and repair both photoproducts. The study evaluates the molecular effects of topical application of a film-forming medical device containing photolyase and UV filters on the precancerous field in AK from seven patients. Skin improvement after treatment was confirmed in all patients by histopathological and molecular assessment. A gene set analysis showed that skin recovery was associated with biological processes involved in tissue homoeostasis and cell maintenance. The CFC response was associated with over-expression of the CPI-17 gene, and a dependence on the initial expression level was observed (P = 0.001). Low CPI-17 levels were directly associated with pro-inflammatory genes such as TNF (P = 0.012) and IL-1B (P = 0.07). Our results suggest a role for CPI-17 in restoring skin homoeostasis in CFC lesions. </p>10aAdministration, Topical10aAdult10aAged10aAged, 80 and over10aBiopsy10aDeoxyribodipyrimidine Photo-Lyase10aFemale10aGene Expression Profiling10aGene Expression Regulation, Enzymologic10aGene Expression Regulation, Neoplastic10aHomeostasis10aHumans10aInflammation10aIntracellular Signaling Peptides and Proteins10aLiposomes10aMale10aMiddle Aged10aMuscle Proteins10aPhenotype10aPhosphoprotein Phosphatases10aReactive Oxygen Species10aSkin10aSkin Neoplasms10aUltraviolet Rays1 aPuig-Butille, Joan, Anton1 aMalvehy, Josep1 aPotrony, Miriam1 aTrullas, Carles1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aPuig, Susana  uhttp://clinbioinfosspa.es/content/role-cpi-17-restoring-skin-homoeostasis-cutaneous-field-cancerization-effects-topical02616nas a2200325   4500008004100000022001400041245012100055210006900176260001600245300000900261490000700270520154400277653002101821653001901842653002901861653002001890653003401910653001301944653001101957653003201968100002402000700002002024700001902044700001902063700002402082700001902106700002002125700002002145856012502165       2012                        eng d  a1362-496200aDiscovering the hidden sub-network component in a ranked list of genes or proteins derived from genomic experiments.0 aDiscovering the hidden subnetwork component in a ranked list of   c2012 Nov 01  ae1580 v403 a<p>Genomic experiments (e.g. differential gene expression, single-nucleotide polymorphism association) typically produce ranked list of genes. We present a simple but powerful approach which uses protein-protein interaction data to detect sub-networks within such ranked lists of genes or proteins. We performed an exhaustive study of network parameters that allowed us concluding that the average number of components and the average number of nodes per component are the parameters that best discriminate between real and random networks. A novel aspect that increases the efficiency of this strategy in finding sub-networks is that, in addition to direct connections, also connections mediated by intermediate nodes are considered to build up the sub-networks. The possibility of using of such intermediate nodes makes this approach more robust to noise. It also overcomes some limitations intrinsic to experimental designs based on differential expression, in which some nodes are invariant across conditions. The proposed approach can also be used for candidate disease-gene prioritization. Here, we demonstrate the usefulness of the approach by means of several case examples that include a differential expression analysis in Fanconi Anemia, a genome-wide association study of bipolar disorder and a genome-scale study of essentiality in cancer genes. An efficient and easy-to-use web interface (available at http://www.babelomics.org) based on HTML5 technologies is also provided to run the algorithm and represent the network.</p>10aBipolar Disorder10aFanconi Anemia10aGene Regulatory Networks10aGenes, Neoplasm10aGenome-Wide Association Study10aGenomics10aHumans10aProtein Interaction Mapping1 aGarcía-Alonso, Luz1 aAlonso, Roberto1 aVidal, Enrique1 aAmadoz, Alicia1 aDe Maria, Alejandro1 aMinguez, Pablo1 aMedina, Ignacio1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/discovering-hidden-sub-network-component-ranked-list-genes-or-proteins-derived-genomic02970nas a2200313   4500008004100000022001400041245008300055210006900138260000900207300001100216490000600227520199700233653001202230653003302242653001102275653001702286653000902303653001802312653004402330653002502374653001902399653002702418100001902445700001902464700002002483700002002503700002002523856011302543       2012                        eng d  a1932-620300aExtensive translatome remodeling during ER stress response in mammalian cells.0 aExtensive translatome remodeling during ER stress response in ma  c2012  ae359150 v73 a<p>In this work we have described the translatome of two mammalian cell lines, NIH3T3 and Jurkat, by scoring the relative polysome association of ∼10,000 mRNA under normal and ER stress conditions. We have found that translation efficiencies of mRNA correlated poorly with transcript abundance, although a general tendency was observed so that the highest translation efficiencies were found in abundant mRNA. Despite the differences found between mouse (NIH3T3) and human (Jurkat) cells, both cell types share a common translatome composed by ∼800-900 mRNA that encode proteins involved in basic cellular functions. Upon stress, an extensive remodeling in translatomes was observed so that translation of ∼50% of mRNA was inhibited in both cell types, this effect being more dramatic for those mRNA that accounted for most of the cell translation. Interestingly, we found two subsets comprising 1000-1500 mRNA whose translation resisted or was induced by stress. Translation arrest resistant class includes many mRNA encoding aminoacyl tRNA synthetases, ATPases and enzymes involved in DNA replication and stress response such as BiP. This class of mRNA is characterized by high translation rates in both control and stress conditions. Translation inducible class includes mRNA whose translation was relieved after stress, showing a high enrichment in early response transcription factors of bZIP and zinc finger C2H2 classes. Unlike yeast, a general coordination between changes in translation and transcription upon stress (potentiation) was not observed in mammalian cells. Among the different features of mRNA analyzed, we found a relevant association of translation efficiency with the presence of upstream ATG in the 5'UTR and with the length of coding sequence of mRNA, and a looser association with other parameters such as the length and the G+C content of 5'UTR. A model for translatome remodeling during the acute phase of stress response in mammalian cells is proposed.</p>10aAnimals10aEndoplasmic Reticulum Stress10aHumans10aJurkat Cells10aMice10aNIH 3T3 Cells10aOligonucleotide Array Sequence Analysis10aProtein Biosynthesis10aRNA, Messenger10aTranscription, Genetic1 aVentoso, Iván1 aKochetov, Alex1 aMontaner, David1 aDopazo, Joaquin1 aSantoyo, Javier  uhttp://clinbioinfosspa.es/content/extensive-translatome-remodeling-during-er-stress-response-mammalian-cells02486nas a2200373   4500008004100000022001400041245014600055210006900201260001600270300000800286490000600294520125600300653001101556653003801567653003401605653001301639653002501652653001101677653000901688100002701697700001701724700002701741700002001768700002301788700002401811700002001835700002001855700002801875700002001903700002501923700002001948700001901968856012501987       2012                        eng d  a1750-117200aFour new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung's disease.0 aFour new loci associations discovered by pathwaybased and networ  c2012 Dec 28  a1030 v73 a<p>Finding gene associations in rare diseases is frequently hampered by the reduced numbers of patients accessible. Conventional gene-based association tests rely on the availability of large cohorts, which constitutes a serious limitation for its application in this scenario. To overcome this problem we have used here a combined strategy in which a pathway-based analysis (PBA) has been initially conducted to prioritize candidate genes in a Spanish cohort of 53 trios of short-segment Hirschsprung's disease. Candidate genes have been further validated in an independent population of 106 trios. The study revealed a strong association of 11 gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other HSCR-related processes. Among the preselected candidates, a total of 4 loci, RASGEF1A, IQGAP2, DLC1 and CHRNA7, related to signal transduction and migration processes, were found to be significantly associated to HSCR. Network analysis also confirms their involvement in the network of already known disease genes. This approach, based on the study of functionally-related gene sets, requires of lower sample sizes and opens new opportunities for the study of rare diseases.</p>10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHirschsprung Disease10aHumans10aMale1 aFernández, Raquel, Ma1 aBleda, Marta1 aNúñez-Torres, Rocío1 aMedina, Ignacio1 aLuzón-Toro, Berta1 aGarcía-Alonso, Luz1 aTorroglosa, Ana1 aMarbà, Martina1 aEnguix-Riego, Ma, Valle1 aMontaner, David1 aAntiňolo, Guillermo1 aDopazo, Joaquin1 aBorrego, Salud  uhttp://clinbioinfosspa.es/content/four-new-loci-associations-discovered-pathway-based-and-network-analyses-genome-wide-003355nas a2200529   4500008004100000022001400041245009200055210007000147260001300217300001100230490000600241520169800247653001801945653001801963653002301981653001502004653002602019653001302045653001702058653003002075653003002105653001702135653001102152653002102163653002702184653005002211653002202261653001202283653001502295653002702310653001502337653004402352653002102396653002402417100002002441700002402461700001802485700002002503700002902523700002002552700002202572700002302594700002302617700003002640700002202670856013302692       2012                        eng d  a2629-327700aIL1β induces mesenchymal stem cells migration and leucocyte chemotaxis through NF-κB.0 aIL1β induces mesenchymal stem cells migration and leucocyte chem  c2012 Sep  a905-160 v83 a<p>Mesenchymal stem cells are often transplanted into inflammatory environments where they are able to survive and modulate host immune responses through a poorly understood mechanism. In this paper we analyzed the responses of MSC to IL-1β: a representative inflammatory mediator. Microarray analysis of MSC treated with IL-1β revealed that this cytokine activateds a set of genes related to biological processes such as cell survival, cell migration, cell adhesion, chemokine production, induction of angiogenesis and modulation of the immune response. Further more detailed analysis by real-time PCR and functional assays revealed that IL-1β mainly increaseds the production of chemokines such as CCL5, CCL20, CXCL1, CXCL3, CXCL5, CXCL6, CXCL10, CXCL11 and CX(3)CL1, interleukins IL-6, IL-8, IL23A, IL32, Toll-like receptors TLR2, TLR4, CLDN1, metalloproteins MMP1 and MMP3, growth factors CSF2 and TNF-α, together with adhesion molecules ICAM1 and ICAM4. Functional analysis of MSC proliferation, migration and adhesion to extracellular matrix components revealed that IL-1β did not affect proliferation but also served to induce the secretion of trophic factors and adhesion to ECM components such as collagen and laminin. IL-1β treatment enhanced the ability of MSC to recruit monocytes and granulocytes in vitro. Blockade of NF-κβ transcription factor activation with IκB kinase beta (IKKβ) shRNA impaired MSC migration, adhesion and leucocyte recruitment, induced by IL-1β demonstrating that NF-κB pathway is an important downstream regulator of these responses. These findings are relevant to understanding the biological responses of MSC to inflammatory environments.</p>10aCell Adhesion10aCell Movement10aCell Proliferation10aChemokines10aChemotaxis, Leukocyte10aCollagen10aFibronectins10aGene Expression Profiling10aGene Knockdown Techniques10aHEK293 Cells10aHumans10aI-kappa B Kinase10aInflammation Mediators10aIntercellular Signaling Peptides and Proteins10aInterleukin-1beta10aLaminin10aLeukocytes10aMesenchymal Stem Cells10aNF-kappa B10aOligonucleotide Array Sequence Analysis10aRNA Interference10aSignal Transduction1 aCarrero, Rubén1 aCerrada, Inmaculada1 aLledó, Elisa1 aDopazo, Joaquin1 aGarcia-Garcia, Francisco1 aRubio, Mari-Paz1 aTrigueros, César1 aDorronsoro, Akaitz1 aRuiz-Sauri, Amparo1 aMontero, José, Anastasio1 aSepúlveda, Pilar  uhttp://clinbioinfosspa.es/content/il1%CE%B2-induces-mesenchymal-stem-cells-migration-and-leucocyte-chemotaxis-through-nf-%CE%BAb02231nas a2200325   4500008004100000022001400041245010200055210006900157260001300226300001100239490000700250520119100257653002301448653001101471653001301482653002701495653001401522653003601536653002501572653001301597100002001610700002101630700001801651700002801669700001801697700002001715700002301735700002301758856012401781       2012                        eng d  a1362-496200aSNPeffect 4.0: on-line prediction of molecular and structural effects of protein-coding variants.0 aSNPeffect 40 online prediction of molecular and structural effec  c2012 Jan  aD935-90 v403 a<p>Single nucleotide variants (SNVs) are, together with copy number variation, the primary source of variation in the human genome and are associated with phenotypic variation such as altered response to drug treatment and susceptibility to disease. Linking structural effects of non-synonymous SNVs to functional outcomes is a major issue in structural bioinformatics. The SNPeffect database (http://snpeffect.switchlab.org) uses sequence- and structure-based bioinformatics tools to predict the effect of protein-coding SNVs on the structural phenotype of proteins. It integrates aggregation prediction (TANGO), amyloid prediction (WALTZ), chaperone-binding prediction (LIMBO) and protein stability analysis (FoldX) for structural phenotyping. Additionally, SNPeffect holds information on affected catalytic sites and a number of post-translational modifications. The database contains all known human protein variants from UniProt, but users can now also submit custom protein variants for a SNPeffect analysis, including automated structure modeling. The new meta-analysis application allows plotting correlations between phenotypic features for a user-selected set of variants.</p>10aDatabases, Protein10aHumans10aInternet10aMeta-Analysis as Topic10aPhenotype10aPolymorphism, Single Nucleotide10aProtein Conformation10aProteins1 aDe Baets, Greet1 aVan Durme, Joost1 aReumers, Joke1 aMaurer-Stroh, Sebastian1 aVanhee, Peter1 aDopazo, Joaquin1 aSchymkowitz, Joost1 aRousseau, Frederic  uhttp://clinbioinfosspa.es/content/snpeffect-40-line-prediction-molecular-and-structural-effects-protein-coding-variants02869nas a2200493   4500008004100000022001400041245007000055210006800125260001600193300001100209490000600220520139500226653001801621653002701639653002101666653004101687653002001728653002401748653000901772653001101781653001801792653004201810653001101852653003701863653001301900653003801913653002701951653001301978100001701991700001902008700001802027700002502045700002102070700002002091700001902111700002602130700002302156700001802179700001602197700002402213700002002237700002002257856009802277       2012                        eng d  a1559-230800aWhole-genome bisulfite DNA sequencing of a DNMT3B mutant patient.0 aWholegenome bisulfite DNA sequencing of a DNMT3B mutant patient  c2012 Jun 01  a542-500 v73 a<p>The immunodeficiency, centromere instability and facial anomalies (ICF) syndrome is associated to mutations of the DNA methyl-transferase DNMT3B, resulting in a reduction of enzyme activity. Aberrant expression of immune system genes and hypomethylation of pericentromeric regions accompanied by chromosomal instability were determined as alterations driving the disease phenotype. However, so far only technologies capable to analyze single loci were applied to determine epigenetic alterations in ICF patients. In the current study, we performed whole-genome bisulphite sequencing to assess alteration in DNA methylation at base pair resolution. Genome-wide we detected a decrease of methylation level of 42%, with the most profound changes occurring in inactive heterochromatic regions, satellite repeats and transposons. Interestingly, transcriptional active loci and ribosomal RNA repeats escaped global hypomethylation. Despite a genome-wide loss of DNA methylation the epigenetic landscape and crucial regulatory structures were conserved. Remarkably, we revealed a mislocated activity of mutant DNMT3B to H3K4me1 loci resulting in hypermethylation of active promoters. Functionally, we could associate alterations in promoter methylation with the ICF syndrome immunodeficient phenotype by detecting changes in genes related to the B-cell receptor mediated maturation pathway.</p>10aB-Lymphocytes10aCell Line, Transformed10aChild, Preschool10aDNA (Cytosine-5-)-Methyltransferases10aDNA Methylation10aEpigenesis, Genetic10aFace10aFemale10aGenome, Human10aHigh-Throughput Nucleotide Sequencing10aHumans10aImmunologic Deficiency Syndromes10amutation10aPrimary Immunodeficiency Diseases10aSequence Analysis, DNA10aSulfites1 aHeyn, Holger1 aVidal, Enrique1 aSayols, Sergi1 aSanchez-Mut, Jose, V1 aMoran, Sebastian1 aMedina, Ignacio1 aSandoval, Juan1 aSimó-Riudalbas, Laia1 aSzczesna, Karolina1 aHuertas, Dori1 aGatto, Sole1 aMatarazzo, Maria, R1 aDopazo, Joaquin1 aEsteller, Manel  uhttp://clinbioinfosspa.es/content/whole-genome-bisulfite-dna-sequencing-dnmt3b-mutant-patient02499nas a2200277   4500008004100000022001400041245005900055210005600114260001300170300001200183490000700195520165100202653001501853653002801868653003001896653003101926653001101957653002001968653004401988100002002032700003002052700002002082700002002102700001602122856008302138       2011                        eng d  a1549-546900aDifferential expression in RNA-seq: a matter of depth.0 aDifferential expression in RNAseq a matter of depth  c2011 Dec  a2213-230 v213 a<p>Next-generation sequencing (NGS) technologies are revolutionizing genome research, and in particular, their application to transcriptomics (RNA-seq) is increasingly being used for gene expression profiling as a replacement for microarrays. However, the properties of RNA-seq data have not been yet fully established, and additional research is needed for understanding how these data respond to differential expression analysis. In this work, we set out to gain insights into the characteristics of RNA-seq data analysis by studying an important parameter of this technology: the sequencing depth. We have analyzed how sequencing depth affects the detection of transcripts and their identification as differentially expressed, looking at aspects such as transcript biotype, length, expression level, and fold-change. We have evaluated different algorithms available for the analysis of RNA-seq and proposed a novel approach--NOISeq--that differs from existing methods in that it is data-adaptive and nonparametric. Our results reveal that most existing methodologies suffer from a strong dependency on sequencing depth for their differential expression calls and that this results in a considerable number of false positives that increases as the number of reads grows. In contrast, our proposed method models the noise distribution from the actual data, can therefore better adapt to the size of the data set, and is more effective in controlling the rate of false discoveries. This work discusses the true potential of RNA-seq for studying regulation at low expression ranges, the noise within RNA-seq data, and the issue of replication.</p>10aAlgorithms10aExpressed Sequence Tags10aGene Expression Profiling10aGene Expression Regulation10aHumans10aModels, Genetic10aOligonucleotide Array Sequence Analysis1 aTarazona, Sonia1 aGarcía-Alcalde, Fernando1 aDopazo, Joaquin1 aFerrer, Alberto1 aConesa, Ana  uhttp://clinbioinfosspa.es/content/differential-expression-rna-seq-matter-depth02371nas a2200289   4500008004100000022001400041245012000055210006900175260001300244300001000257490000700267520143700274653001201711653002301723653002501746653002101771653002001792653001101812653001101823653000901834653002201843100002401865700002001889700002301909700002001932856012901952       2011                        eng d  a1477-405400aEvidence for short-time divergence and long-time conservation of tissue-specific expression after gene duplication.0 aEvidence for shorttime divergence and longtime conservation of t  c2011 Sep  a442-80 v123 a<p>Gene duplication is one of the main mechanisms by which genomes can acquire novel functions. It has been proposed that the retention of gene duplicates can be associated to processes of tissue expression divergence. These models predict that acquisition of divergent expression patterns should be acquired shortly after the duplication, and that larger divergence in tissue expression would be expected for paralogs, as compared to orthologs of a similar age. Many studies have shown that gene duplicates tend to have divergent expression patterns and that gene family expansions are associated with high levels of tissue specificity. However, the timeframe in which these processes occur have rarely been investigated in detail, particularly in vertebrates, and most analyses do not include direct comparisons of orthologs as a baseline for the expected levels of tissue specificity in absence of duplications. To assess the specific contribution of duplications to expression divergence, we combine here phylogenetic analyses and expression data from human and mouse. In particular, we study differences in spatial expression among human-mouse paralogs, specifically duplicated after the radiation of mammals, and compare them to pairs of orthologs in the same species. Our results show that gene duplication leads to increased levels of tissue specificity and that this tends to occur promptly after the duplication event.</p>10aAnimals10aConserved Sequence10aEvolution, Molecular10aGene Duplication10agene expression10aGenome10aHumans10aMice10aOrgan Specificity1 aHuerta-Cepas, Jaime1 aDopazo, Joaquin1 aHuynen, Martijn, A1 aGabaldón, Toni  uhttp://clinbioinfosspa.es/content/evidence-short-time-divergence-and-long-time-conservation-tissue-specific-expression-after03586nas a2200649   4500008004100000022001400041245019000055210006900245260001600314300001200330490000700342520147500349653001801824653002201842653001201864653004901876653002501925653001401950653001701964653002101981653002502002653002002027653001902047653003002066653002902096653001102125653000902136653001802145653002802163653002802191653005202219653002902271653002402300653003002324653004802354653001802402100001402420700001802434700003002452700001602482700002002498700002002518700001702538700002402555700001902579700001902598700002802617700002002645700001902665700002802684700001802712700002202730700002002752700002002772700001902792856012502811       2011                        eng d  a1460-208300aLarge-scale transcriptional profiling and functional assays reveal important roles for Rho-GTPase signalling and SCL during haematopoietic differentiation of human embryonic stem cells.0 aLargescale transcriptional profiling and functional assays revea  c2011 Dec 15  a4932-460 v203 a<p>Understanding the transcriptional cues that direct differentiation of human embryonic stem cells (hESCs) and human-induced pluripotent stem cells to defined and functional cell types is essential for future clinical applications. In this study, we have compared transcriptional profiles of haematopoietic progenitors derived from hESCs at various developmental stages of a feeder- and serum-free differentiation method and show that the largest transcriptional changes occur during the first 4 days of differentiation. Data mining on the basis of molecular function revealed Rho-GTPase signalling as a key regulator of differentiation. Inhibition of this pathway resulted in a significant reduction in the numbers of emerging haematopoietic progenitors throughout the differentiation window, thereby uncovering a previously unappreciated role for Rho-GTPase signalling during human haematopoietic development. Our analysis indicated that SCL was the 11th most upregulated transcript during the first 4 days of the hESC differentiation process. Overexpression of SCL in hESCs promoted differentiation to meso-endodermal lineages, the emergence of haematopoietic and erythro-megakaryocytic progenitors and accelerated erythroid differentiation. Importantly, intrasplenic transplantation of SCL-overexpressing hESC-derived haematopoietic cells enhanced recovery from induced acute anaemia without significant cell engraftment, suggesting a paracrine-mediated effect.</p>10aAcute Disease10aAnemia, Hemolytic10aAnimals10aBasic Helix-Loop-Helix Transcription Factors10aCell Differentiation10aCell Line10aCell Lineage10aCluster Analysis10aEmbryonic Stem Cells10aErythroid Cells10aFlow Cytometry10aGene Expression Profiling10aHematopoietic Stem Cells10aHumans10aMice10aMyeloid Cells10aParacrine Communication10aProto-Oncogene Proteins10aReverse Transcriptase Polymerase Chain Reaction10arho GTP-Binding Proteins10aSignal Transduction10aStem Cell Transplantation10aT-Cell Acute Lymphocytic Leukemia Protein 110aTranscriptome1 aYung, Sun1 aLedran, Maria1 aMoreno-Gimeno, Inmaculada1 aConesa, Ana1 aMontaner, David1 aDopazo, Joaquin1 aDimmick, Ian1 aSlater, Nicholas, J1 aMarenah, Lamin1 aReal, Pedro, J1 aParaskevopoulou, Iliana1 aBisbal, Viviana1 aBurks, Deborah1 aSantibanez-Koref, Mauro1 aMoreno, Ruben1 aMountford, Joanne1 aMenendez, Pablo1 aArmstrong, Lyle1 aLako, Majlinda  uhttp://clinbioinfosspa.es/content/large-scale-transcriptional-profiling-and-functional-assays-reveal-important-roles-rho02919nas a2200433   4500008004100000022001400041245013300055210006900188260000900257300001100266490000600277520154700283653001201830653002801842653001001870653002201880653001101902653002301913653001101936653001201947653001301959653001301972653002301985653004402008653003002052653003102082653002502113653001802138100003302156700001902189700002202208700002002230700002002250700002002270700002002290700002002310700002502330856013002355       2011                        eng d  a1932-620300aMutation screening of multiple genes in Spanish patients with autosomal recessive retinitis pigmentosa by targeted resequencing.0 aMutation screening of multiple genes in Spanish patients with au  c2011  ae278940 v63 a<p>Retinitis Pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. RP is the leading cause of visual loss in individuals younger than 60 years, with a prevalence of about 1 in 4000. The molecular genetic diagnosis of autosomal recessive RP (arRP) is challenging due to the large genetic and clinical heterogeneity. Traditional methods for sequencing arRP genes are often laborious and not easily available and a screening technique that enables the rapid detection of the genetic cause would be very helpful in the clinical practice. The goal of this study was to develop and apply microarray-based resequencing technology capable of detecting both known and novel mutations on a single high-throughput platform. Hence, the coding regions and exon/intron boundaries of 16 arRP genes were resequenced using microarrays in 102 Spanish patients with clinical diagnosis of arRP. All the detected variations were confirmed by direct sequencing and potential pathogenicity was assessed by functional predictions and frequency in controls. For validation purposes 4 positive controls for variants consisting of previously identified changes were hybridized on the array. As a result of the screening, we detected 44 variants, of which 15 are very likely pathogenic detected in 14 arRP families (14%). Finally, the design of this array can easily be transformed in an equivalent diagnostic system based on targeted enrichment followed by next generation sequencing.</p>10aAlleles10aDNA Mutational Analysis10aExons10aGenetic Variation10aGenome10aHispanic or Latino10aHumans10aIntrons10aLanguage10amutation10aMutation, Missense10aOligonucleotide Array Sequence Analysis10aPolymerase Chain Reaction10aReproducibility of Results10aRetinitis pigmentosa10aUnited States1 adel Pozo, María, González-1 aBorrego, Salud1 aBarragán, Isabel1 aPieras, Juan, I1 aSantoyo, Javier1 aMatamala, Nerea1 aNaranjo, Belén1 aDopazo, Joaquin1 aAntiňolo, Guillermo  uhttp://clinbioinfosspa.es/content/mutation-screening-multiple-genes-spanish-patients-autosomal-recessive-retinitis-pigmentosa03406nas a2200529   4500008004100000022001400041245007000055210006900125260000900194300000800203490000700211520186600218653000902084653002102093653001602114653002002130653002402150653001102174653003002185653001502215653001302230653001102243653001802254653001602272653001302288653002102301653004402322653002102366653003302387100002302420700002502443700001902468700001902487700002002506700002202526700002002548700002602568700002002594700002002614700002202634700002602656700001902682700002002701700002802721700002702749856010002776       2010                        eng d  a1465-542X00aDNA methylation epigenotypes in breast cancer molecular subtypes.0 aDNA methylation epigenotypes in breast cancer molecular subtypes  c2010  aR770 v123 a<p><b>INTRODUCTION: </b>Identification of gene expression based breast cancer subtypes is considered as a critical means of prognostication. Genetic mutations along with epigenetic alterations contribute to gene expression changes occurring in breast cancer. So far, these epigenetic contributions to sporadic breast cancer subtypes have not been well characterized, and there is only a limited understanding of the epigenetic mechanisms affected in those particular breast cancer subtypes. The present study was undertaken to dissect the breast cancer methylome and deliver specific epigenotypes associated with particular breast cancer subtypes.</p><p><b>METHODS: </b>Using a microarray approach we analyzed DNA methylation in regulatory regions of 806 cancer related genes in 28 breast cancer paired samples. We subsequently performed substantial technical and biological validation by Pyrosequencing, investigating the top qualifying 19 CpG regions in independent cohorts encompassing 47 basal-like, 44 ERBB2+ overexpressing, 48 luminal A and 48 luminal B paired breast cancer/adjacent tissues. Using all-subset selection method, we identified the most subtype predictive methylation profiles in multivariable logistic regression analysis.</p><p><b>RESULTS: </b>The approach efficiently recognized 15 individual CpG loci differentially methylated in breast cancer tumor subtypes. We further identify novel subtype specific epigenotypes which clearly demonstrate the differences in the methylation profiles of basal-like and human epidermal growth factor 2 (HER2)-overexpressing tumors.</p><p><b>CONCLUSIONS: </b>Our results provide evidence that well defined DNA methylation profiles enables breast cancer subtype prediction and support the utilization of this biomarker for prognostication and therapeutic stratification of patients with breast cancer.</p>10aAged10aBreast Neoplasms10aCpG Islands10aDNA Methylation10aEpigenesis, Genetic10aFemale10aGene Expression Profiling10aGenes, p5310aGenotype10aHumans10aKi-67 Antigen10aMiddle Aged10amutation10aNeoplasm Grading10aOligonucleotide Array Sequence Analysis10aReceptor, ErbB-210aTumor Suppressor Protein p531 aBediaga, Naiara, G1 aAcha-Sagredo, Amelia1 aGuerra, Isabel1 aViguri, Amparo1 aAlbaina, Carmen1 aDiaz, Irune, Ruiz1 aRezola, Ricardo1 aAlberdi, Maria, Jesus1 aDopazo, Joaquin1 aMontaner, David1 aRenobales, Mertxe1 aFernandez, Agustin, F1 aField, John, K1 aFraga, Mario, F1 aLiloglou, Triantafillos1 ade Pancorbo, Marian, M  uhttp://clinbioinfosspa.es/content/dna-methylation-epigenotypes-breast-cancer-molecular-subtypes03755nas a2200625   4500008004100000022001400041245009800055210006900153260001600222300001100238490000600249520178700255653001002042653004902052653001102101653002102112653004902133653002502182653002902207653002402236653002802260653001102288653001902299653003802318653003402356653001302390653002302403653001102426653001502437653001102452653003602463653003702499653002902536653003802565653002002603653002002623653002002643653001702663100002102680700002002701700002402721700002702745700002102772700002202793700002202815700002502837700001702862700002002879700002102899700001902920700001902939700002102958700002602979856012403005       2010                        eng d  a1932-620300aExploring the link between germline and somatic genetic alterations in breast carcinogenesis.0 aExploring the link between germline and somatic genetic alterati  c2010 Nov 22  ae140780 v53 a<p>Recent genome-wide association studies (GWASs) have identified candidate genes contributing to cancer risk through low-penetrance mutations. Many of these genes were unexpected and, intriguingly, included well-known players in carcinogenesis at the somatic level. To assess the hypothesis of a germline-somatic link in carcinogenesis, we evaluated the distribution of somatic gene labels within the ordered results of a breast cancer risk GWAS. This analysis suggested frequent influence on risk of genetic variation in loci encoding for "driver kinases" (i.e., kinases encoded by genes that showed higher somatic mutation rates than expected by chance and, therefore, whose deregulation may contribute to cancer development and/or progression). Assessment of these predictions using a population-based case-control study in Poland replicated the association for rs3732568 in EPHB1 (odds ratio (OR) = 0.79; 95% confidence interval (CI): 0.63-0.98; P(trend) = 0.031). Analyses by early age at diagnosis and by estrogen receptor α (ERα) tumor status indicated potential associations for rs6852678 in CDKL2 (OR = 0.32, 95% CI: 0.10-1.00; P(recessive) = 0.044) and rs10878640 in DYRK2 (OR = 2.39, 95% CI: 1.32-4.30; P(dominant) = 0.003), and for rs12765929, rs9836340, rs4707795 in BMPR1A, EPHA3 and EPHA7, respectively (ERα tumor status P(interaction)<0.05). The identification of three novel candidates as EPH receptor genes might indicate a link between perturbed compartmentalization of early neoplastic lesions and breast cancer risk and progression. Together, these data may lay the foundations for replication in additional populations and could potentially increase our knowledge of the underlying molecular mechanisms of breast carcinogenesis.</p>10aAdult10aBone Morphogenetic Protein Receptors, Type I10aBreast10aBreast Neoplasms10aCalcium-Calmodulin-Dependent Protein Kinases10aCase-Control Studies10aCyclin-Dependent Kinases10aDisease Progression10aEstrogen Receptor alpha10aFemale10aGene Frequency10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aGerm-Line Mutation10aHumans10aOdds Ratio10aPoland10aPolymorphism, Single Nucleotide10aProtein Serine-Threonine Kinases10aProtein-Tyrosine Kinases10aReceptor Protein-Tyrosine Kinases10aReceptor, EphA310aReceptor, EphA710aReceptor, EphB110aRisk Factors1 aBonifaci, Núria1 aGórski, Bohdan1 aMasojć, Bartlomiej1 aWokołorczyk, Dominika1 aJakubowska, Anna1 aDębniak, Tadeusz1 aBerenguer, Antoni1 aMusach, Jordi, Serra1 aBrunet, Joan1 aDopazo, Joaquin1 aNarod, Steven, A1 aLubiński, Jan1 aLázaro, Conxi1 aCybulski, Cezary1 aPujana, Miguel, Angel  uhttp://clinbioinfosspa.es/content/exploring-link-between-germline-and-somatic-genetic-alterations-breast-carcinogenesis03015nas a2200541   4500008004100000022001400041245013100055210006900186260001300255300001100268490000700279520146000286653001501746653002301761653002701784653003001811653001301841653001101854653003001865653004401895653001401939653003001953653001301983653002001996100001102016700001902027700001802046700001302064700001802077700001802095700002102113700001402134700001602148700001802164700001202182700001402194700001202208700001202220700001102232700001402243700001802257700001702275700001702292700001202309700001102321700001602332856012502348       2010                        eng d  a1473-115000aFunctional analysis of multiple genomic signatures demonstrates that classification algorithms choose phenotype-related genes.0 aFunctional analysis of multiple genomic signatures demonstrates   c2010 Aug  a310-230 v103 a<p>Gene expression signatures of toxicity and clinical response benefit both safety assessment and clinical practice; however, difficulties in connecting signature genes with the predicted end points have limited their application. The Microarray Quality Control Consortium II (MAQCII) project generated 262 signatures for ten clinical and three toxicological end points from six gene expression data sets, an unprecedented collection of diverse signatures that has permitted a wide-ranging analysis on the nature of such predictive models. A comprehensive analysis of the genes of these signatures and their nonredundant unions using ontology enrichment, biological network building and interactome connectivity analyses demonstrated the link between gene signatures and the biological basis of their predictive power. Different signatures for a given end point were more similar at the level of biological properties and transcriptional control than at the gene level. Signatures tended to be enriched in function and pathway in an end point and model-specific manner, and showed a topological bias for incoming interactions. Importantly, the level of biological similarity between different signatures for a given end point correlated positively with the accuracy of the signature predictions. These findings will aid the understanding, and application of predictive genomic signatures, and support their broader application in predictive medicine.</p>10aAlgorithms10aDatabases, Genetic10aEndpoint Determination10aGene Expression Profiling10aGenomics10aHumans10aNeural Networks, Computer10aOligonucleotide Array Sequence Analysis10aPhenotype10aPredictive Value of Tests10aProteins10aQuality Control1 aShi, W1 aBessarabova, M1 aDosymbekov, D1 aDezso, Z1 aNikolskaya, T1 aDudoladova, M1 aSerebryiskaya, T1 aBugrim, A1 aGuryanov, A1 aBrennan, R, J1 aShah, R1 aDopazo, J1 aChen, M1 aDeng, Y1 aShi, T1 aJurman, G1 aFurlanello, C1 aThomas, R, S1 aCorton, J, C1 aTong, W1 aShi, L1 aNikolsky, Y  uhttp://clinbioinfosspa.es/content/functional-analysis-multiple-genomic-signatures-demonstrates-classification-algorithms02384nas a2200301   4500008004100000022001400041245010100055210006900156260001600225300001100241490000600252520140600258653001601664653002301680653003001703653001301733653001101746653004401757100001801801700002001819700001801839700002001857700001901877700002401896700002001920700001801940856012401958       2010                        eng d  a1932-620300aFunctional genomics of 5- to 8-cell stage human embryos by blastomere single-cell cDNA analysis.0 aFunctional genomics of 5 to 8cell stage human embryos by blastom  c2010 Oct 26  ae136150 v53 a<p>Blastomere fate and embryonic genome activation (EGA) during human embryonic development are unsolved areas of high scientific and clinical interest. Forty-nine blastomeres from 5- to 8-cell human embryos have been investigated following an efficient single-cell cDNA amplification protocol to provide a template for high-density microarray analysis. The previously described markers, characteristic of Inner Cell Mass (ICM) (n = 120), stemness (n = 190) and Trophectoderm (TE) (n = 45), were analyzed, and a housekeeping pattern of 46 genes was established. All the human blastomeres from the 5- to 8-cell stage embryo displayed a common gene expression pattern corresponding to ICM markers (e.g., DDX3, FOXD3, LEFTY1, MYC, NANOG, POU5F1), stemness (e.g., POU5F1, DNMT3B, GABRB3, SOX2, ZFP42, TERT), and TE markers (e.g., GATA6, EOMES, CDX2, LHCGR). The EGA profile was also investigated between the 5-6- and 8-cell stage embryos, and compared to the blastocyst stage. Known genes (n = 92) such as depleted maternal transcripts (e.g., CCNA1, CCNB1, DPPA2) and embryo-specific activation (e.g., POU5F1, CDH1, DPPA4), as well as novel genes, were confirmed. In summary, the global single-cell cDNA amplification microarray analysis of the 5- to 8-cell stage human embryos reveals that blastomere fate is not committed to ICM or TE. Finally, new EGA features in human embryogenesis are presented.</p>10aBlastomeres10aDNA, Complementary10aGene Expression Profiling10aGenomics10aHumans10aOligonucleotide Array Sequence Analysis1 aGalan, Amparo1 aMontaner, David1 aPóo, Eugenia1 aValbuena, Diana1 aRuiz, Veronica1 aAguilar, Cristóbal1 aDopazo, Joaquin1 aSimon, Carlos  uhttp://clinbioinfosspa.es/content/functional-genomics-5-8-cell-stage-human-embryos-blastomere-single-cell-cdna-analysis03317nas a2200613   4500008004100000022001400041245010400055210006900159260001600228300001100244490000700255520144400262653001901706653001201725653001501737653002801752653002501780653001701805653002501822653002001847653002001867653002501887653002201912653003001934653003101964653001101995653000902006653002602015653003602041653001102077653002702088653000902115653001502124653004102139100002302180700001602203700001902219700003002238700002702268700002102295700002002316700002002336700001702356700002002373700002702393700002202420700001802442700002902460700001802489700002002507700002202527700002302549856013102572       2010                        eng d  a1549-491800aHypoxia promotes efficient differentiation of human embryonic stem cells to functional endothelium.0 aHypoxia promotes efficient differentiation of human embryonic st  c2010 Mar 31  a407-180 v283 a<p>Early development of mammalian embryos occurs in an environment of relative hypoxia. Nevertheless, human embryonic stem cells (hESC), which are derived from the inner cell mass of blastocyst, are routinely cultured under the same atmospheric conditions (21% O(2)) as somatic cells. We hypothesized that O(2) levels modulate gene expression and differentiation potential of hESC, and thus, we performed gene profiling of hESC maintained under normoxic or hypoxic (1% or 5% O(2)) conditions. Our analysis revealed that hypoxia downregulates expression of pluripotency markers in hESC but increases significantly the expression of genes associated with angio- and vasculogenesis including vascular endothelial growth factor and angiopoitein-like proteins. Consequently, we were able to efficiently differentiate hESC to functional endothelial cells (EC) by varying O(2) levels; after 24 hours at 5% O(2), more than 50% of cells were CD34+. Transplantation of resulting endothelial-like cells improved both systolic function and fractional shortening in a rodent model of myocardial infarction. Moreover, analysis of the infarcted zone revealed that transplanted EC reduced the area of fibrous scar tissue by 50%. Thus, use of hypoxic conditions to specify the endothelial lineage suggests a novel strategy for cellular therapies aimed at repair of damaged vasculature in pathologies such as cerebral ischemia and myocardial infarction.</p>10aAngiopoietin-110aAnimals10abiomarkers10aCell Culture Techniques10aCell Differentiation10aCell Hypoxia10aCell Transplantation10aCells, Cultured10aDown-Regulation10aEmbryonic Stem Cells10aEndothelial Cells10aGene Expression Profiling10aGene Expression Regulation10aHumans10aMale10aMyocardial Infarction10aNeovascularization, Physiologic10aOxygen10aPluripotent Stem Cells10aRats10aRats, Nude10aVascular Endothelial Growth Factor A1 aPrado-Lopez, Sonia1 aConesa, Ana1 aArmiñán, Ana1 aMartínez-Losa, Magdalena1 aEscobedo-Lucea, Carmen1 aGandia, Carolina1 aTarazona, Sonia1 aMelguizo, Dario1 aBlesa, David1 aMontaner, David1 aSanz-González, Silvia1 aSepúlveda, Pilar1 aGötz, Stefan1 aO'Connor, José, Enrique1 aMoreno, Ruben1 aDopazo, Joaquin1 aBurks, Deborah, J1 aStojkovic, Miodrag  uhttp://clinbioinfosspa.es/content/hypoxia-promotes-efficient-differentiation-human-embryonic-stem-cells-functional-endothelium02107nas a2200241   4500008004100000022001400041245005600055210005500111260001600166300001100182490000600193520139200199653002301591653003001614653002901644653001801673653001301691653001101704653002401715100002001739700002001759856008601779       2010                        eng d  a1932-620300aMultidimensional gene set analysis of genomic data.0 aMultidimensional gene set analysis of genomic data  c2010 Apr 27  ae103480 v53 a<p>Understanding the functional implications of changes in gene expression, mutations, etc., is the aim of most genomic experiments. To achieve this, several functional profiling methods have been proposed. Such methods study the behaviour of different gene modules (e.g. gene ontology terms) in response to one particular variable (e.g. differential gene expression). In spite to the wealth of information provided by functional profiling methods, a common limitation to all of them is their inherent unidimensional nature. In order to overcome this restriction we present a multidimensional logistic model that allows studying the relationship of gene modules with different genome-scale measurements (e.g. differential expression, genotyping association, methylation, copy number alterations, heterozygosity, etc.) simultaneously. Moreover, the relationship of such functional modules with the interactions among the variables can also be studied, which produces novel results impossible to be derived from the conventional unidimensional functional profiling methods. We report sound results of gene sets associations that remained undetected by the conventional one-dimensional gene set analysis in several examples. Our findings demonstrate the potential of the proposed approach for the discovery of new cell functionalities with complex dependences on more than one variable.</p>10aDatabases, Genetic10aGene Expression Profiling10aGene Regulatory Networks10aGenome, Human10aGenomics10aHumans10aModels, Statistical1 aMontaner, David1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/multidimensional-gene-set-analysis-genomic-data03040nas a2200565   4500008004100000022001400041245009600055210006900151260001300220300001400233490000700247520132400254653002401578653001201602653002501614653002801639653002401667653002501691653001701716653001101733653002101744653002201765653001101787653000901798653002801807653001301835653001301848653003601861653003201897653002501929653001001954653003301964100002201997700001902019700002602038700003302064700002002097700001802117700002302135700002202158700001802180700002402198700001902222700002102241700002202262700002002284700002702304700002502331856011802356       2010                        eng d  a1098-100400aMutation spectrum of EYS in Spanish patients with autosomal recessive retinitis pigmentosa.0 aMutation spectrum of EYS in Spanish patients with autosomal rece  c2010 Nov  aE1772-8000 v313 a<p>Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. We have recently identified a new gene(EYS) encoding an ortholog of Drosophila space maker (spam) as a commonly mutated gene in autosomal recessive RP. In the present study, we report the identification of 73 sequence variations in EYS, of which 28 are novel. Of these, 42.9% (12/28) are very likely pathogenic, 17.9% (5/28)are possibly pathogenic, whereas 39.3% (11/28) are SNPs. In addition, we have detected 3 pathogenic changes previously reported in other populations. We are also presenting the characterisation of EYS homologues in different species, and a detailed analysis of the EYS domains, with the identification of an interesting novel feature: a putative coiled-coil domain.Majority of the mutations in the arRP patients have been found within the domain structures of EYS. The minimum observed prevalence of distinct EYS mutations in our group of patients is of 15.9% (15/94), confirming a major involvement of EYS in the pathogenesis of arRP in the Spanish population. Along with the detection of three recurrent mutations in Caucasian population, our hypothesis of EYS being the first prevalent gene in arRP has been reinforced in the present study.</p>10aAmino Acid Sequence10aAnimals10aCase-Control Studies10aDNA Mutational Analysis10aDrosophila Proteins10aEvolution, Molecular10aEye Proteins10aFemale10aGenes, Recessive10aGenetic Variation10aHumans10aMale10aMolecular Sequence Data10amutation10aPedigree10aPolymorphism, Single Nucleotide10aProtein Structure, Tertiary10aRetinitis pigmentosa10aSpain10aStructural Homology, Protein1 aBarragán, Isabel1 aBorrego, Salud1 aPieras, Juan, Ignacio1 adel Pozo, María, González-1 aSantoyo, Javier1 aAyuso, Carmen1 aBaiget, Montserrat1 aMillán, José, M1 aMena, Marcela1 aEl-Aziz, Mai, M Abd1 aAudo, Isabelle1 aZeitz, Christina1 aLittink, Karin, W1 aDopazo, Joaquin1 aBhattacharya, Shomi, S1 aAntiňolo, Guillermo  uhttp://clinbioinfosspa.es/content/mutation-spectrum-eys-spanish-patients-autosomal-recessive-retinitis-pigmentosa02417nas a2200469   4500008004100000022001400041245007800055210006900133260001300202300001300215490000700228520094000235653001001175653002101185653003001206653004101236653002601277653001101303653002101314653002201335653004401357653001901401653001801420653002701438100002001465700003001485700002701515700002501542700002101567700002401588700002801612700002601640700002701666700002401693700002201717700002101739700001501760700002001775700002301795700002101818856010801839       2009                        eng d  a1029-240300aFunctional signatures identified in B-cell non-Hodgkin lymphoma profiles.0 aFunctional signatures identified in Bcell nonHodgkin lymphoma pr  c2009 Oct  a1699-7080 v503 a<p>Gene-expression profiling in B-cell lymphomas has provided crucial data on specific lymphoma types, which can contribute to the identification of essential lymphoma survival genes and pathways. In this study, the gene-expression profiling data of all major B-cell lymphoma types were analyzed by unsupervised clustering. The transcriptome classification so obtained, was explored using gene set enrichment analysis generating a heatmap for B-cell lymphoma that identifies common lymphoma survival mechanisms and potential therapeutic targets, recognizing sets of coregulated genes and functional pathways expressed in different lymphoma types. Some of the most relevant signatures (stroma, cell cycle, B-cell receptor (BCR)) are shared by multiple lymphoma types or subclasses. A specific attention was paid to the analysis of BCR and coregulated pathways, defining molecular heterogeneity within multiple B-cell lymphoma types.</p>10aAdult10aCluster Analysis10aGene Expression Profiling10aGene Expression Regulation, Leukemic10aGenetic Heterogeneity10aHumans10aLymphoma, B-Cell10aNeoplasm Proteins10aOligonucleotide Array Sequence Analysis10aRNA, Messenger10aRNA, Neoplasm10aTranscription, Genetic1 aAggarwal, Mohit1 aSánchez-Beato, Margarita1 aGómez-López, Gonzalo1 aAl-Shahrour, Fátima1 aMartínez, Nerea1 aRodríguez, Antonia1 aRuiz-Ballesteros, Elena1 aCamacho, Francisca, I1 aPérez-Rosado, Alberto1 ade la Cueva, Paloma1 aArtiga, María, J1 aPisano, David, G1 aKimby, Eva1 aDopazo, Joaquin1 aVilluendas, Raquel1 aPiris, Miguel, A  uhttp://clinbioinfosspa.es/content/functional-signatures-identified-b-cell-non-hodgkin-lymphoma-profiles03382nas a2200325   4500008004100000022001400041245007200055210006900127260001600196300000800212490000700220520234600227653001502573653002102588653004402609653002602653653002802679653001102707653003002718653001302748653001102761653004402772653003002816653003102846100002002877700001902897700002502916700002002941856009502961       2009                        eng d  a1471-216400aGene set internal coherence in the context of functional profiling.0 aGene set internal coherence in the context of functional profili  c2009 Apr 27  a1970 v103 a<p><b>BACKGROUND: </b>Functional profiling methods have been extensively used in the context of high-throughput experiments and, in particular, in microarray data analysis. Such methods use available biological information to define different types of functional gene modules (e.g. gene ontology -GO-, KEGG pathways, etc.) whose representation in a pre-defined list of genes is further studied. In the most popular type of microarray experimental designs (e.g. up- or down-regulated genes, clusters of co-expressing genes, etc.) or in other genomic experiments (e.g. Chip-on-chip, epigenomics, etc.) these lists are composed by genes with a high degree of co-expression. Therefore, an implicit assumption in the application of functional profiling methods within this context is that the genes corresponding to the modules tested are effectively defining sets of co-expressing genes. Nevertheless not all the functional modules are biologically coherent entities in terms of co-expression, which will eventually hinder its detection with conventional methods of functional enrichment.</p><p><b>RESULTS: </b>Using a large collection of microarray data we have carried out a detailed survey of internal correlation in GO terms and KEGG pathways, providing a coherence index to be used for measuring functional module co-regulation. An unexpected low level of internal correlation was found among the modules studied. Only around 30% of the modules defined by GO terms and 57% of the modules defined by KEGG pathways display an internal correlation higher than the expected by chance.This information on the internal correlation of the genes within the functional modules can be used in the context of a logistic regression model in a simple way to improve their detection in gene expression experiments.</p><p><b>CONCLUSION: </b>For the first time, an exhaustive study on the internal co-expression of the most popular functional categories has been carried out. Interestingly, the real level of coexpression within many of them is lower than expected (or even inexistent), which will preclude its detection by means of most conventional functional profiling methods. If the gene-to-function correlation information is used in functional profiling methods, the results obtained improve the ones obtained by conventional enrichment methods.</p>10aAlgorithms10aBreast Neoplasms10aCarcinoma, Intraductal, Noninfiltrating10aComputational Biology10aDatabases, Nucleic Acid10aFemale10aGene Expression Profiling10aGenomics10aHumans10aOligonucleotide Array Sequence Analysis10aPapillomavirus Infections10aReproducibility of Results1 aMontaner, David1 aMinguez, Pablo1 aAl-Shahrour, Fátima1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/gene-set-internal-coherence-context-functional-profiling02023nas a2200349   4500008004100000022001400041245014400055210006900199260001300268300001100281490000700292520085700299653002501156653002101181653001101202653001001213653002201223653003401245653001101279653003601290653001301326653002801339100002001367700002001387700002101407700002601428700002101454700002301475700002501498700002001523856013001543       2009                        eng d  a1362-496200aGene set-based analysis of polymorphisms: finding pathways or biological processes associated to traits in genome-wide association studies.0 aGene setbased analysis of polymorphisms finding pathways or biol  c2009 Jul  aW340-40 v373 a<p>Genome-wide association studies have become a popular strategy to find associations of genes to traits of interest. Despite the high-resolution available today to carry out genotyping studies, the success of its application in real studies has been limited by the testing strategy used. As an alternative to brute force solutions involving the use of very large cohorts, we propose the use of the Gene Set Analysis (GSA), a different analysis strategy based on testing the association of modules of functionally related genes. We show here how the Gene Set-based Analysis of Polymorphisms (GeSBAP), which is a simple implementation of the GSA strategy for the analysis of genome-wide association studies, provides a significant increase in the power testing for this type of studies. GeSBAP is freely available at http://bioinfo.cipf.es/gesbap/.</p>10aBiological Phenomena10aBreast Neoplasms10aFemale10aGenes10aGenetic Variation10aGenome-Wide Association Study10aHumans10aPolymorphism, Single Nucleotide10aSoftware10aUser-Computer Interface1 aMedina, Ignacio1 aMontaner, David1 aBonifaci, Núria1 aPujana, Miguel, Angel1 aCarbonell, José1 aTárraga, Joaquín1 aAl-Shahrour, Fátima1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/gene-set-based-analysis-polymorphisms-finding-pathways-or-biological-processes-associated-001732nas a2200277   4500008004100000022001400041245009700055210006900152260001300221300001200234490000700246520083000253653002201083653003701105653002301142653001101165653001301176653003201189653001301221100001901234700001801253700002001271700002501291700002001316856011801336       2009                        eng d  a1362-496200aSNOW, a web-based tool for the statistical analysis of protein-protein interaction networks.0 aSNOW a webbased tool for the statistical analysis of proteinprot  c2009 Jul  aW109-140 v373 a<p>Understanding the structure and the dynamics of the complex intercellular network of interactions that contributes to the structure and function of a living cell is one of the main challenges of today's biology. SNOW inputs a collection of protein (or gene) identifiers and, by using the interactome as scaffold, draws the connections among them, calculates several relevant network parameters and, as a novelty among the rest of tools of its class, it estimates their statistical significance. The parameters calculated for each node are: connectivity, betweenness and clustering coefficient. It also calculates the number of components, number of bicomponents and articulation points. An interactive network viewer is also available to explore the resulting network. SNOW is available at http://snow.bioinfo.cipf.es.</p>10aComputer Graphics10aData Interpretation, Statistical10aDatabases, Protein10aHumans10aInternet10aProtein Interaction Mapping10aSoftware1 aMinguez, Pablo1 aGötz, Stefan1 aMontaner, David1 aAl-Shahrour, Fátima1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/snow-web-based-tool-statistical-analysis-protein-protein-interaction-networks-001946nas a2200337   4500008004100000022001400041245010400055210006900159260001300228300001100241490000700252520087500259653002101134653002601155653002301181653001101204653003001215653001101245653002701256653002601283653001401309100001601323700001601339700002901355700002501384700001801409700002001427700002001447700002001467856012101487       2008                        eng d  a1089-864600aDirect functional assessment of the composite phenotype through multivariate projection strategies.0 aDirect functional assessment of the composite phenotype through   c2008 Dec  a373-830 v923 a<p>We present a novel approach for the analysis of transcriptomics data that integrates functional annotation of gene sets with expression values in a multivariate fashion, and directly assesses the relation of functional features to a multivariate space of response phenotypical variables. Multivariate projection methods are used to obtain new correlated variables for a set of genes that share a given function. These new functional variables are then related to the response variables of interest. The analysis of the principal directions of the multivariate regression allows for the identification of gene function features correlated with the phenotype. Two different transcriptomics studies are used to illustrate the statistical and interpretative aspects of the methodology. We demonstrate the superiority of the proposed method over equivalent approaches.</p>10aBreast Neoplasms10aComputational Biology10aDatabases, Genetic10aFemale10aGene Expression Profiling10aHumans10aMathematical Computing10aMultivariate Analysis10aPhenotype1 aConesa, Ana1 aBro, Rasmus1 aGarcia-Garcia, Francisco1 aPrats, José, Manuel1 aGötz, Stefan1 aKjeldahl, Karin1 aMontaner, David1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/direct-functional-assessment-composite-phenotype-through-multivariate-projection-001564nas a2200229   4500008004100000022001400041245003200055210003100087260000900118300001100127490000800138520093500146653001201081653002601093653002001119653003001139653001101169653004401180100002001224700002501244856006501269       2008                        eng d  a1064-374500aExpression and microarrays.0 aExpression and microarrays  c2008  a245-550 v4533 a<p>High throughput methodologies have increased by several orders of magnitude the amount of experimental microarray data available. Nevertheless, translating these data into useful biological knowledge remains a challenge. There is a risk of perceiving these methodologies as mere factories that produce never-ending quantities of data if a proper biological interpretation is not provided. Methods of interpreting these data are continuously evolving. Typically, a simple two-step approach has been used, in which genes of interest are first selected based on thresholds for the experimental values, and then enrichment in biologically relevant terms in the annotations of these genes is analyzed in a second step. For various reasons, such methods are quite poor in terms of performance and new procedures inspired by systems biology that directly address sets of functionally related genes are currently under development.</p>10aAnimals10aComputational Biology10agene expression10aGene Expression Profiling10aHumans10aOligonucleotide Array Sequence Analysis1 aDopazo, Joaquin1 aAl-Shahrour, Fátima  uhttp://clinbioinfosspa.es/content/expression-and-microarrays02956nas a2200409   4500008004100000022001400041245013400055210006900189260001300258300001100271490000700282520167500289653002801964653001201992653002302004653002902027653003002056653001102086653001302097653000902110653001402119653001302133653003602146653001302182653000902195653002102204653002602225100001802251700001702269700002002286700002802306700002102334700002002355700002302375700002302398856012502421       2008                        eng d  a1362-496200aJoint annotation of coding and non-coding single nucleotide polymorphisms and mutations in the SNPeffect and PupaSuite databases.0 aJoint annotation of coding and noncoding single nucleotide polym  c2008 Jan  aD825-90 v363 a<p>Single nucleotide polymorphisms (SNPs) are, together with copy number variation, the primary source of variation in the human genome. SNPs are associated with altered response to drug treatment, susceptibility to disease and other phenotypic variation. Furthermore, during genetic screens for disease-associated mutations in groups of patients and control individuals, the distinction between disease causing mutation and polymorphism is often unclear. Annotation of the functional and structural implications of single nucleotide changes thus provides valuable information to interpret and guide experiments. The SNPeffect and PupaSuite databases are now synchronized to deliver annotations for both non-coding and coding SNP, as well as annotations for the SwissProt set of human disease mutations. In addition, SNPeffect now contains predictions of Tango2: an improved aggregation detector, and Waltz: a novel predictor of amyloid-forming sequences, as well as improved predictors for regions that are recognized by the Hsp70 family of chaperones. The new PupaSuite version incorporates predictions for SNPs in silencers and miRNAs including their targets, as well as additional methods for predicting SNPs in TFBSs and splice sites. Also predictions for mouse and rat genomes have been added. In addition, a PupaSuite web service has been developed to enable data access, programmatically. The combined database holds annotations for 4,965,073 regulatory as well as 133,505 coding human SNPs and 14,935 disease mutations, and phenotypic descriptions of 43,797 human proteins and is accessible via http://snpeffect.vib.be and http://pupasuite.bioinfo.cipf.es/.</p>10aAmino Acid Substitution10aAnimals10aDatabases, Genetic10aGenetic Diseases, Inborn10aHSP70 Heat-Shock Proteins10aHumans10aInternet10aMice10aMicroRNAs10amutation10aPolymorphism, Single Nucleotide10aProteins10aRats10aRNA Splice Sites10aTranscription Factors1 aReumers, Joke1 aConde, Lucia1 aMedina, Ignacio1 aMaurer-Stroh, Sebastian1 aVan Durme, Joost1 aDopazo, Joaquin1 aRousseau, Frederic1 aSchymkowitz, Joost  uhttp://clinbioinfosspa.es/content/joint-annotation-coding-and-non-coding-single-nucleotide-polymorphisms-and-mutations-003267nas a2200517   4500008004100000022001400041245013100055210006900186260001600255300001200271490000700283520168900290653001201979653001501991653001002006653000902016653002202025653001402047653002502061653002502086653001102111653003002122653004302152653001102195653000902206653001602215653004402231653001402275653005202289653001802341653002402359653002202383100002102405700002502426700001302451700001502464700002902479700001702508700001602525700002002541700001402561700001602575700001502591700001602606856012702622       2008                        eng d  a1476-559400aMolecular profiling related to poor prognosis in thyroid carcinoma. Combining gene expression data and biological information.0 aMolecular profiling related to poor prognosis in thyroid carcino  c2008 Mar 06  a1554-610 v273 a<p>Undifferentiated and poorly differentiated thyroid tumors are responsible for more than half of thyroid cancer patient deaths in spite of their low incidence. Conventional treatments do not obtain substantial benefits, and the lack of alternative approaches limits patient survival. Additionally, the absence of prognostic markers for well-differentiated tumors complicates patient-specific treatments and favors the progression of recurrent forms. In order to recognize the molecular basis involved in tumor dedifferentiation and identify potential markers for thyroid cancer prognosis prediction, we analysed the expression profile of 44 thyroid primary tumors with different degrees of dedifferentiation and aggressiveness using cDNA microarrays. Transcriptome comparison of dedifferentiated and well-differentiated thyroid tumors identified 1031 genes with >2-fold difference in absolute values and false discovery rate of <0.15. According to known molecular interaction and reaction networks, the products of these genes were mainly clustered in the MAPkinase signaling pathway, the TGF-beta signaling pathway, focal adhesion and cell motility, activation of actin polymerization and cell cycle. An exhaustive search in several databases allowed us to identify various members of the matrix metalloproteinase, melanoma antigen A and collagen gene families within the upregulated gene set. We also identified a prognosis classifier comprising just 30 transcripts with an overall accuracy of 95%. These findings may clarify the molecular mechanisms involved in thyroid tumor dedifferentiation and provide a potential prognosis predictor as well as targets for new therapies.</p>10aAdenoma10aAdolescent10aAdult10aAged10aBiomarkers, Tumor10aCarcinoma10aCarcinoma, Papillary10aCell Differentiation10aFemale10aGene Expression Profiling10aGene Expression Regulation, Neoplastic10aHumans10aMale10aMiddle Aged10aOligonucleotide Array Sequence Analysis10aPrognosis10aReverse Transcriptase Polymerase Chain Reaction10aRNA, Neoplasm10aSignal Transduction10aThyroid Neoplasms1 aMontero-Conde, C1 aMartín-Campos, J, M1 aLerma, E1 aGimenez, G1 aMartínez-Guitarte, J, L1 aCombalía, N1 aMontaner, D1 aMatías-Guiu, X1 aDopazo, J1 ade Leiva, A1 aRobledo, M1 aMauricio, D  uhttp://clinbioinfosspa.es/content/molecular-profiling-related-poor-prognosis-thyroid-carcinoma-combining-gene-expression-002125nas a2200301   4500008004100000022001400041245007500055210006900130260001300199300001100212490000700223520123800230653001801468653002101486653001001507653001301517653002101530653001101551653001401562653001301576653002901589653002301618100002401641700001801665700002001683700002001703856010001723       2008                        eng d  a1362-496200aPhylomeDB: a database for genome-wide collections of gene phylogenies.0 aPhylomeDB a database for genomewide collections of gene phylogen  c2008 Jan  aD491-60 v363 a<p>The complete collection of evolutionary histories of all genes in a genome, also known as phylome, constitutes a valuable source of information. The reconstruction of phylomes has been previously prevented by large demands of time and computer power, but is now feasible thanks to recent developments in computers and algorithms. To provide a publicly available repository of complete phylomes that allows researchers to access and store large-scale phylogenomic analyses, we have developed PhylomeDB. PhylomeDB is a database of complete phylomes derived for different genomes within a specific taxonomic range. All phylomes in the database are built using a high-quality phylogenetic pipeline that includes evolutionary model testing and alignment trimming phases. For each genome, PhylomeDB provides the alignments, phylogentic trees and tree-based orthology predictions for every single encoded protein. The current version of PhylomeDB includes the phylomes of Human, the yeast Saccharomyces cerevisiae and the bacterium Escherichia coli, comprising a total of 32 289 seed sequences with their corresponding alignments and 172 324 phylogenetic trees. PhylomeDB can be publicly accessed at http://phylomedb.bioinfo.cipf.es.</p>10aBase Sequence10aEscherichia coli10aGenes10aGenomics10aHistory, Ancient10aHumans10aPhylogeny10aProteins10aSaccharomyces cerevisiae10aSequence Alignment1 aHuerta-Cepas, Jaime1 aBueno, Anibal1 aDopazo, Joaquin1 aGabaldón, Toni  uhttp://clinbioinfosspa.es/content/phylomedb-database-genome-wide-collections-gene-phylogenies-003089nas a2200385   4500008004100000022001400041245013400055210006900189260001300258300001200271490000700283520182800290653001502118653001002133653002602143653002302169653002802192653002502220653003802245653002202283653001802305653001102323653001802334653001902352653003602371653001302407653003302420100002202453700002102475700001802496700002002514700002002534700002502554856012402579       2008                        eng d  a1098-100400aUse of estimated evolutionary strength at the codon level improves the prediction of disease-related protein mutations in humans.0 aUse of estimated evolutionary strength at the codon level improv  c2008 Jan  a198-2040 v293 a<p>Predicting the functional impact of protein variation is one of the most challenging problems in bioinformatics. A rapidly growing number of genome-scale studies provide large amounts of experimental data, allowing the application of rigorous statistical approaches for predicting whether a given single point mutation has an impact on human health. Up until now, existing methods have limited their source data to either protein or gene information. Novel in this work, we take advantage of both and focus on protein evolutionary information by using estimated selective pressures at the codon level. Here we introduce a new method (SeqProfCod) to predict the likelihood that a given protein variant is associated with human disease or not. Our method relies on a support vector machine (SVM) classifier trained using three sources of information: protein sequence, multiple protein sequence alignments, and the estimation of selective pressure at the codon level. SeqProfCod has been benchmarked with a large dataset of 8,987 single point mutations from 1,434 human proteins from SWISS-PROT. It achieves 82% overall accuracy and a correlation coefficient of 0.59, indicating that the estimation of the selective pressure helps in predicting the functional impact of single-point mutations. Moreover, this study demonstrates the synergic effect of combining two sources of information for predicting the functional effects of protein variants: protein sequence/profile-based information and the evolutionary estimation of the selective pressures at the codon level. The results of large-scale application of SeqProfCod over all annotated point mutations in SWISS-PROT (available for download at http://sgu.bioinfo.cipf.es/services/Omidios/; last accessed: 24 August 2007), could be used to support clinical studies.</p>10aAlgorithms10aCodon10aComputational Biology10aDatabases, Protein10aDNA Mutational Analysis10aEvolution, Molecular10aGenetic Predisposition to Disease10aGenetic Variation10aGenome, Human10aHumans10aIduronic Acid10aPoint Mutation10aPolymorphism, Single Nucleotide10aProteins10aTumor Suppressor Protein p531 aCapriotti, Emidio1 aArbiza, Leonardo1 aCasadio, Rita1 aDopazo, Joaquin1 aDopazo, Hernán1 aMarti-Renom, Marc, A  uhttp://clinbioinfosspa.es/content/use-estimated-evolutionary-strength-codon-level-improves-prediction-disease-related-002985nas a2200421   4500008004100000022001400041245007000055210006800125260001600193300000800209490000600217520169900223653003601922653003001958653004301988653001102031653000902042653002302051653002002074653002402094653002202118653001402140653002402154653003202178653001902210653002402229653002002253100002202273700002402295700002002319700002502339700001602364700001702380700002202397700002002419700002602439856009802465       2007                        eng d  a1471-216400aEvidence for systems-level molecular mechanisms of tumorigenesis.0 aEvidence for systemslevel molecular mechanisms of tumorigenesis  c2007 Jun 20  a1850 v83 a<p><b>BACKGROUND: </b>Cancer arises from the consecutive acquisition of genetic alterations. Increasing evidence suggests that as a consequence of these alterations, molecular interactions are reprogrammed in the context of highly connected and regulated cellular networks. Coordinated reprogramming would allow the cell to acquire the capabilities for malignant growth.</p><p><b>RESULTS: </b>Here, we determine the coordinated function of cancer gene products (i.e., proteins encoded by differentially expressed genes in tumors relative to healthy tissue counterparts, hereafter referred to as "CGPs") defined as their topological properties and organization in the interactome network. We show that CGPs are central to information exchange and propagation and that they are specifically organized to promote tumorigenesis. Centrality is identified by both local (degree) and global (betweenness and closeness) measures, and systematically appears in down-regulated CGPs. Up-regulated CGPs do not consistently exhibit centrality, but both types of cancer products determine the overall integrity of the network structure. In addition to centrality, down-regulated CGPs show topological association that correlates with common biological processes and pathways involved in tumorigenesis.</p><p><b>CONCLUSION: </b>Given the current limited coverage of the human interactome, this study proposes that tumorigenesis takes place in a specific and organized way at the molecular systems-level and suggests a model that comprises the precise down-regulation of groups of topologically-associated proteins involved in particular functions, orchestrated with the up-regulation of specific proteins.</p>10aCell Transformation, Neoplastic10aGene Expression Profiling10aGene Expression Regulation, Neoplastic10aHumans10aMale10aModels, Biological10aModels, Genetic10aModels, Statistical10aNeoplasm Proteins10aNeoplasms10aProstatic Neoplasms10aProtein Interaction Mapping10aRNA, Messenger10aSignal Transduction10aSystems biology1 aHernández, Pilar1 aHuerta-Cepas, Jaime1 aMontaner, David1 aAl-Shahrour, Fátima1 aValls, Joan1 aGómez, Laia1 aCapellà, Gabriel1 aDopazo, Joaquin1 aPujana, Miguel, Angel  uhttp://clinbioinfosspa.es/content/evidence-systems-level-molecular-mechanisms-tumorigenesis-002675nas a2200385   4500008004100000022001400041245016600055210006900221260001300290300001000303490000700313520140700320653002201727653001201749653001801761653002601779653003001805653001001835653001301845653001101858653001301869653004401882653002601926653001301952653002401965653002601989100002502015700001902040700002302059700002002082700001602102700002002118700002002138856013102158       2007                        eng d  a1362-496200aFatiGO +: a functional profiling tool for genomic data. Integration of functional annotation, regulatory motifs and interaction data with microarray experiments.0 aFatiGO a functional profiling tool for genomic data Integration   c2007 Jul  aW91-60 v353 a<p>The ultimate goal of any genome-scale experiment is to provide a functional interpretation of the data, relating the available information with the hypotheses that originated the experiment. Thus, functional profiling methods have become essential in diverse scenarios such as microarray experiments, proteomics, etc. We present the FatiGO+, a web-based tool for the functional profiling of genome-scale experiments, specially oriented to the interpretation of microarray experiments. In addition to different functional annotations (gene ontology, KEGG pathways, Interpro motifs, Swissprot keywords and text-mining based bioentities related to diseases and chemical compounds) FatiGO+ includes, as a novelty, regulatory and structural information. The regulatory information used includes predictions of targets for distinct regulatory elements (obtained from the Transfac and CisRed databases). Additionally FatiGO+ uses predictions of target motifs of miRNA to infer which of these can be activated or deactivated in the sample of genes studied. Finally, properties of gene products related to their relative location and connections in the interactome have also been used. Also, enrichment of any of these functional terms can be directly analysed on chromosomal coordinates. FatiGO+ can be found at: http://www.fatigoplus.org and within the Babelomics environment http://www.babelomics.org.</p>10aAmino Acid Motifs10aAnimals10aBinding Sites10aComputational Biology10aGene Expression Profiling10aGenes10aGenomics10aHumans10aInternet10aOligonucleotide Array Sequence Analysis10aProgramming Languages10aSoftware10aSystems Integration10aTranscription Factors1 aAl-Shahrour, Fátima1 aMinguez, Pablo1 aTárraga, Joaquín1 aMedina, Ignacio1 aAlloza, Eva1 aMontaner, David1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/fatigo-functional-profiling-tool-genomic-data-integration-functional-annotation-regulatory-002054nas a2200385   4500008004100000022001400041245012300055210006900178260001300247300001000260490000700270520079500277653001201072653002101084653002601105653002201131653003001153653001101183653001301194653002001207653003101227653004401258653002601302653001301328653002401341653002801365100001701393700002001410700002701430700002301457700002001480700002501500700002001525856012301545       2007                        eng d  a1362-496200aISACGH: a web-based environment for the analysis of Array CGH and gene expression which includes functional profiling.0 aISACGH a webbased environment for the analysis of Array CGH and   c2007 Jul  aW81-50 v353 a<p>We present the ISACGH, a web-based system that allows for the combination of genomic data with gene expression values and provides different options for functional profiling of the regions found. Several visualization options offer a convenient representation of the results. Different efficient methods for accurate estimation of genomic copy number from array-CGH hybridization data have been included in the program. Moreover, the connection to the gene expression analysis package GEPAS allows the use of different facilities for data pre-processing and analysis. A DAS server allows exporting the results to the Ensembl viewer where contextual genomic information can be obtained. The program is freely available at: http://isacgh.bioinfo.cipf.es or within http://www.gepas.org.</p>10aAnimals10aCluster Analysis10aComputational Biology10aComputer Graphics10aGene Expression Profiling10aHumans10aInternet10aModels, Genetic10aNucleic Acid Hybridization10aOligonucleotide Array Sequence Analysis10aProgramming Languages10aSoftware10aSystems Integration10aUser-Computer Interface1 aConde, Lucia1 aMontaner, David1 aBurguet-Castell, Jordi1 aTárraga, Joaquín1 aMedina, Ignacio1 aAl-Shahrour, Fátima1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/isacgh-web-based-environment-analysis-array-cgh-and-gene-expression-which-includes-0