03233nas a2200613 4500008004100000022001400041245014900055210006900204260001200273300001200285490000800297520129600305653002101601653002601622653001301648653001001661653003101671653003201702653001101734653000901745653003301754653002101787653001901808653002201827653001301849653002601862653003401888653002701922100003001949700002701979700002802006700001702034700001902051700001902070700002102089700002902110700002202139700001902161700002402180700002202204700002102226700001902247700002102266700002202287700001702309700001902326700002002345700002602365700003002391700001902421700002602440700001902466856013402485 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
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.
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 uhttps://www.clinbioinfosspa.es/content/de-novo-small-deletion-affecting-transcription-start-site-short-isoform-auts2-gene-patient02761nas a2200385 4500008004100000022001400041245015900055210006900214260001500283300001000298490000700308520150900315653001601824653001301840653001101853653001101864653002601875653000901901653002601910653001001936653002201946653001401968100002001982700002402002700002702026700003102053700002102084700002602105700002902131700001802160700002002178700002002198700002802218856012902246 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 aCOVID-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.
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 uhttps://www.clinbioinfosspa.es/content/real-world-evidence-calcifediol-or-vitamin-d-prescription-and-mortality-rate-covid-1902937nas a2200613 4500008004100000022001400041245012600055210006900181260001500250300001500265490000700280520120500287653001801492653001101510653001301521653001101534653002101545653000901566653001401575653002001589653001301609653001501622653001801637100001301655700002401668700001201692700001701704700001601721700001701737700001601754700001601770700001201786700001401798700001601812700001501828700002101843700002101864700002201885700001501907700002301922700002101945700002101966700001601987700001602003700002102019700002502040700001902065700001702084700001402101700001802115700002602133710003102159856013302190 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 aCancer 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.
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 uhttps://www.clinbioinfosspa.es/content/community-assessment-predictability-cancer-protein-and-phosphoprotein-levels-genomics-and02321nas a2200241 4500008004100000022001400041245014100055210006900196260001500265490000600280520146700286653001101753653004301764653001101807653000901818653001401827653002401841100001801865700001801883700002401901700002001925856013401945 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 aDespite 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.
10aFemale10aGene Expression Regulation, Neoplastic10aHumans10aMale10aNeoplasms10aSignal Transduction1 aCubuk, Cankut1 aCan, Fatma, E1 aPeña-Chilet, Maria1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/mechanistic-models-signaling-pathways-reveal-drug-action-mechanisms-behind-gender-specific03275nas a2200493 4500008004100000022001400041245012000055210006900175260001200244490000600256520175600262653001002018653000902028653004102037653001102078653001102089653000902100653001602109653001402125653001202139653001402151653001602165100002502181700001702206700002302223700002902246700002002275700002202295700002402317700002502341700002402366700002302390700002502413700002802438700002202466700001902488700002402507700002002531700002702551700002502578700002002603700002602623856013202649 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 aBACKGROUND: 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).
METHODS: 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).
RESULTS: 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%).
CONCLUSIONS: 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.
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 uhttps://www.clinbioinfosspa.es/content/nivolumab-and-sunitinib-combination-advanced-soft-tissue-sarcomas-multicenter-single-arm05180nas a2201117 4500008004100000022001400041245011300055210006900168260001200237300001200249490000700261520174900268653001402017653003102031653001502062653002502077653001902102653005102121653001102172653002902183653003802212653001102250653000902261653002302270653003602293653002702329100002202356700001702378700002402395700002802419700003302447700002702480700001502507700002402522700002902546700002602575700002802601700001702629700002002646700002102666700001902687700002702706700001902733700002002752700002402772700003002796700001902826700002602845700002902871700001802900700002102918700002202939700003202961700002002993700002603013700002903039700002103068700002203089700002103111700001903132700002703151700002403178700002903202700003203231700002003263700001803283700003103301700002803332700001603360700002503376700003103401700003303432700002903465700002203494700002103516700002403537700001903561700002503580700001703605700001703622700001803639700002303657700002003680700001603700700002203716700002503738700001803763700002303781700002003804700002003824700002103844700003303865700001703898700002103915856012603936 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 aPURPOSE: 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.
METHODS: 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.
RESULTS: 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.
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 uhttps://www.clinbioinfosspa.es/content/optimised-molecular-genetic-diagnostics-fanconi-anaemia-whole-exome-sequencing-and04661nas a2200625 4500008004100000022001400041245010700055210006900162260001200231300001200243490000700255520277400262653000903036653001103045653002203056653001103078653001403089653000903103653001603112653002403128653001403152653002403166653003003190653001603220653004903236653002803285653001703313653001803330100002503348700001903373700001903392700001903411700001703430700001603447700002003463700002103483700002203504700003403526700002003560700002403580700002303604700001903627700002003646700002003666700002503686700002303711700002203734700002003756700002903776700003203805700002103837700002003858700002403878856013303902 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 aBACKGROUND: 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.
METHODS: 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.
FINDINGS: 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%]).
INTERPRETATION: 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.
FUNDING: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.
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 uhttps://www.clinbioinfosspa.es/content/pazopanib-treatment-typical-solitary-fibrous-tumours-multicentre-single-arm-phase-2-trial05146nas a2200745 4500008004100000022001400041245013000055210006900185260001200254300001200266490000800278520304400286653001503330653001003345653001103355653001203366653002503378653002003403653001003423653002103433653002603454653003803480653002503518653003403543653001103577653001603588653001303604653003103617653002303648653001103671653001103682653002003693653000903713653001603722653001303738653002503751653003103776653002503807653001203832653000903844653002603853653001603879100002203895700001303917700001303930700002303943700001503966700001903981700002404000700001604024700001604040700002904056700001404085700001504099700002704114700002404141700001404165700001204179700001604191700001504207700001504222700001404237700001504251856013404266 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 aBACKGROUND: 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.
OBJECTIVES: To investigate, by means of comparative gene expression analysis, the role played by dermal fibroblasts in the pathogenesis of RDEB, KS and XPC.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
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 uhttps://www.clinbioinfosspa.es/content/fibroblast-activation-and-abnormal-extracellular-matrix-remodelling-common-hallmarks-three05186nas a2200661 4500008004100000022001400041245013800055210006900193260001200262300001200274490000700286520316900293653001003462653000903472653002803481653002603509653001103535653001103546653001403557653000903571653001603580653002603596653001603622653004903638653002603687653002803713653001703741653002203758100002503780700002403805700002503829700002003854700002103874700002203895700002103917700002203938700002303960700002003983700002404003700002204027700002204049700001804071700001904089700003004108700002904138700002304167700001804190700002904208700002404237700001704261700001504278700002004293700002704313700001804340700002004358700001904378856012704397 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 01 a134-1440 v203 aBACKGROUND: 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.
METHODS: 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.
FINDINGS: 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%]).
INTERPRETATION: 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.
FUNDING: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.
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 uhttps://www.clinbioinfosspa.es/content/pazopanib-treatment-advanced-malignant-and-dedifferentiated-solitary-fibrous-tumour03417nas a2200793 4500008004100000022001400041245009300055210006900148260001500217300000900232490000600241520096600247653001201213653001401225653002301239653001801262653003601280653003001316653001101346653003101357653001101388653002401399653002101423653001201444653002801456653002501484653004101509653001601550653000901566653000901575653002301584653001501607653003901622653001701661653003001678653003401708100002801742700002201770700003201792700002901824700002601853700002601879700003101905700003301936700002201969700003101991700001902022700002002041700002002061700002202081700002002103700002302123700001602146700002302162700002302185700002302208700001902231700002502250700002902275700002102304700002502325700003202350700001602382700001802398700003802416700001702454700002402471856012802495 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 04 16 a14880 v93 aType 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.
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 uhttps://www.clinbioinfosspa.es/content/lrh-1-agonism-favours-immune-islet-dialogue-which-protects-against-diabetes-mellitus02954nas a2200541 4500008004100000022001400041245008900055210006900144260000900213300001300222490000700235520138200242653001001624653000901634653001801643653001101661653002901672653003201701653002601733653001101759653001401770653002901784653000901813653001601822653001301838653002201851653001801873653001401891653002701905100002101932700003101953700002001984700002402004700002402028700002602052700001602078700001902094700001902113700002502132700002002157700001902177700002002196700002002216700002402236700002002260700001902280856011302299 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 aAcute 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.
10aAdult10aAged10aCytodiagnosis10aFemale10aGene Regulatory Networks10aGenetic Association Studies10aGenetic Heterogeneity10aHumans10aKaryotype10aLeukemia, Myeloid, Acute10aMale10aMiddle Aged10amutation10aNeoplasm Proteins10aNucleophosmin10aPrognosis10awhole exome sequencing1 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 uhttps://www.clinbioinfosspa.es/content/modular-network-structure-mutational-landscape-acute-myeloid-leukemia02565nas a2200541 4500008004100000022001400041245008600055210006900141260001200210300001200222490000700234520094000241653002801181653001201209653002801221653001001249653004201259653001301301653001101314653003101325653000901356653001301365653001401378653003301392653002801425100002201453700001701475700002501492700003201517700002201549700001801571700002101589700002001610700002401630700003401654700001901688700002001707700002901727700002501756700001901781700002001800700001901820700001801839700001701857700001901874700001901893856011101912 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 02 a148-1510 v383 aCongenital 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.
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 uhttps://www.clinbioinfosspa.es/content/mutations-trappc11-are-associated-congenital-disorder-glycosylation02499nas a2200505 4500008004100000022001400041245008800055210006900143260001600212300000900228490000600237520111400243653001001357653000901367653002201376653002001398653001601418653001101434653001101445653000901456653001601465653003101481653002201512653002601534100002201560700001201582700001301594700001301607700001401620700002301634700001801657700001701675700002301692700002001715700002001735700001401755700001401769700001301783700001601796700001201812700001401824700001601838700001601854856012301870 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 aDifferent 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.
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 uhttps://www.clinbioinfosspa.es/content/human-dna-methylomes-neurodegenerative-diseases-show-common-epigenomic-patterns03226nas a2200697 4500008004100000022001400041245013600055210006900191260001500260300001000275490000600285520117300291653000901464653001201473653002601485653002001511653001901531653003801550653001801588653002801606653001001634653001701644653001101661653003101672653002101703653002501724653001501749653001101764653000901775653000901784653001601793653003601809653003201845653001101877653002401888653003601912653002501948653001001973653002101983653002602004100001402030700002402044700001602068700001602084700001702100700002402117700002702141700002402168700002102192700001302213700002302226700001402249700002702263700002002290700002302310700001402333700002402347700001402371700001302385856013002398 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 10 13 a353700 v63 aRetinitis 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.
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 uhttps://www.clinbioinfosspa.es/content/identification-photoreceptor-transcriptional-co-repressor-samd11-novel-cause-autosomal03507nas a2200517 4500008004100000022001400041245007400055210006900129260001300198300001000211490000800221520209300229653001002322653000902332653001202341653001002353653003202363653001102395653002002406653001102426653001102437653000902448653000902457653001602466653001302482653001302495653001402508653001802522653001602540653002602556653001602582100002002598700001902618700002902637700001802666700001902684700002502703700002402728700003102752700001802783700002002801700002202821700002002843700002102863856010502884 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 aCharcot-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.
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 uhttps://www.clinbioinfosspa.es/content/mutations-morc2-gene-cause-axonal-charcot-marie-tooth-disease02961nas a2200505 4500008004100000022001400041245008800055210006900143260001300212300001000225490000900235520151700244653001501761653001701776653001001793653002101803653002101824653001001845653001101855653004201866653001101908653001101919653002801930653000901958653001301967653001301980653001401993653001402007653002302021100002002044700002102064700001902085700002902104700002302133700002202156700002202178700001902200700001902219700002002238700001702258700002302275700002102298700002102319856011502340 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 aOpitz 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.
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 uhttps://www.clinbioinfosspa.es/content/screening-cd96-and-asxl1-11-patients-opitz-c-or-bohring-opitz-syndromes02610nas a2200397 4500008004100000022001400041245017300055210006900228260001600297300001300313490000600326520129300332653001001625653000901635653002201644653003501666653002401701653001101725653001101736653001901747653000901766653001701775653001601792653004301808100003001851700002801881700002501909700002901934700001501963700002101978700001601999700002002015700001802035700002702053856013202080 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 aLung 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.
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 uhttps://www.clinbioinfosspa.es/content/serum-metabolomic-profiling-facilitates-non-invasive-identification-metabolic-biomarkers02466nas a2200445 4500008004100000022001400041245006900055210006200124260001300186300001200199490000700211520128200218653001001500653000901510653002201519653001001541653003201551653003601583653001001619653001101629653001101640653000901651653001601660653001301676653001301689653001401702653003001716653001601746100001501762700001401777700002301791700001201814700002001826700001501846700001401861700001901875700001301894700001601907856009701923 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 aBACKGROUND AND PURPOSE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
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 uhttps://www.clinbioinfosspa.es/content/egr2-gene-involved-axonal-charcot-marie-tooth-disease02780nas a2200445 4500008004100000022001400041245012000055210006900175260000900244300001200253490000600265520144600271653001501717653001001732653002401742653001801766653001001784653002701794653002801821653001001849653001101859653001101870653001101881653002501892653000901917653001601926653002801942653001301970653001301983653002401996653001402020100003302034700002802067700002302095700002202118700002002140700001902160700002502179856013002204 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 aThis 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.
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 uhttps://www.clinbioinfosspa.es/content/exome-sequencing-reveals-novel-and-recurrent-mutations-clinical-significance-inherited03200nas a2200517 4500008004100000022001400041245017300055210006900228260001300297300001000310490000700320520152000327653003201847653003101879653001601910653001101926653000901937653002301946653002801969653001501997653002002012100002802032700002302060700001602083700002402099700002502123700002102148700001902169700002202188700002102210700002002231700002002251700002202271700001902293700002102312700002802333700002202361700002002383700001702403700002702420700002602447700002102473700002402494700002802518856013602546 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 aInactivating 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.
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 uhttps://www.clinbioinfosspa.es/content/two-novel-mutations-bckdk-branched-chain-keto-acid-dehydrogenase-kinase-gene-are-responsible02843nas a2200349 4500008004100000022001400041245010300055210006900158260001700227300001100244490000700255520180200262653001002064653001102074653003002085653001102115653000902126653001602135653000902151653003302160653003302193100001502226700001502241700001602256700001202272700001502284700001602299700001402315700001302329700001502342856013602357 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 aAnalysis 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.
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 uhttps://www.clinbioinfosspa.es/content/differential-gene-expression-analysis-defines-molecular-pattern-related-olive-pollen-allergy02660nas a2200421 4500008004100000022001400041245010400055210006900159260001700228300000900245490000800254520136600262653001501628653001001643653003201653653001001685653001001695653001101705653004201716653001101758653001101769653000901780653003001789653001301819100001901832700003401851700002701885700002601912700002801938700002301966700001901989700002902008700002002037700001702057700001802074700001902092856012702111 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 a3-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.
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 uhttps://www.clinbioinfosspa.es/content/exome-sequencing-identifies-new-mutation-serac1-patient-3-methylglutaconic-aciduria03047nas a2200481 4500008004100000022001400041245012800055210006900183260001300252300001100265490000700276520158000283653001201863653001701875653001601892653001901908653001501927653002701942653002501969653001801994653002402012653002002036653001302056653001702069653002502086653002202111653002102133653000902154653000902163653001802172653001002190100002602200700002302226700002002249700002402269700002902293700002002322700002102342700002902363700002202392700002002414856013102434 2013 eng d a1460-218000aGrape antioxidant dietary fiber inhibits intestinal polyposis in ApcMin/+ mice: relation to cell cycle and immune response.0 aGrape antioxidant dietary fiber inhibits intestinal polyposis in c2013 Aug a1881-80 v343 aEpidemiological and experimental studies suggest that fiber and phenolic compounds might have a protective effect on the development of colon cancer in humans. Accordingly, we assessed the chemopreventive efficacy and associated mechanisms of action of a lyophilized red grape pomace containing proanthocyanidin (PA)-rich dietary fiber [grape antioxidant dietary fiber (GADF)] on spontaneous intestinal tumorigenesis in the Apc(Min/+) mouse model. Mice were fed a standard diet (control group) or a 1% (w/w) GADF-supplemented diet (GADF group) for 6 weeks. GADF supplementation greatly reduced intestinal tumorigenesis, significantly decreasing the total number of polyps by 76%. Moreover, size distribution analysis showed a considerable reduction in all polyp size categories [diameter <1mm (65%), 1-2mm (67%) and >2mm (87%)]. In terms of polyp formation in the proximal, middle and distal portions of the small intestine, a decrease of 76, 81 and 73% was observed, respectively. Putative molecular mechanisms underlying the inhibition of intestinal tumorigenesis were investigated by comparison of microarray expression profiles of GADF-treated and non-treated mice. We observed that the effects of GADF are mainly associated with the induction of a G1 cell cycle arrest and the downregulation of genes related to the immune response and inflammation. Our findings show for the first time the efficacy and associated mechanisms of action of GADF against intestinal tumorigenesis in Apc(Min/+) mice, suggesting its potential for the prevention of colorectal cancer.
10aAnimals10aAntioxidants10aBody Weight10aCarcinogenesis10aCell Cycle10aCell Cycle Checkpoints10aColorectal Neoplasms10aDietary Fiber10aDietary Supplements10aDown-Regulation10aG1 Phase10aInflammation10aIntestinal Polyposis10aIntestinal Polyps10aIntestine, Small10aMale10aMice10aTranscriptome10aVitis1 aSánchez-Tena, Susana1 aLizarraga, Daneida1 aMiranda, Anibal1 aVinardell, Maria, P1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aTorres, Josep, L1 aSaura-Calixto, Fulgencio1 aCapellà, Gabriel1 aCascante, Marta uhttps://www.clinbioinfosspa.es/content/grape-antioxidant-dietary-fiber-inhibits-intestinal-polyposis-apcmin-mice-relation-cell02957nas a2200481 4500008004100000022001400041245013400055210006900189260001600258300001100274490000800285520141700293653002801710653002501738653001001763653001501773653001601788653002001804653002001824653003001844653001101874653000901885653001601894653004401910653001901954653001801973100002401991700002402015700002602039700002502065700002402090700002202114700001802136700002002154700002902174700002902203700001802232700002402250700002402274700002502298700002102323856013102344 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 aBACKGROUND: 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.
METHODS AND RESULTS: 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.
CONCLUSIONS: 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.
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 uhttps://www.clinbioinfosspa.es/content/novel-genes-detected-transcriptional-profiling-whole-blood-cells-patients-early-onset-002677nas a2200409 4500008004100000022001400041245006600055210006400121260001600185300000800201490000600209520145600215653001101671653003801682653001301720653002501733653001101758653000901769653003601778100002601814700001701840700002301857700002401880700001901904700002201923700002001945700002401965700001601989700002502005700002302030700002402053700002602077700002502103700002002128700001902148856010002167 2013 eng d a1750-117200aPathways systematically associated to Hirschsprung's disease.0 aPathways systematically associated to Hirschsprungs disease c2013 Dec 02 a1870 v83 aDespite 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.
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 uhttps://www.clinbioinfosspa.es/content/pathways-systematically-associated-hirschsprungs-disease02727nas a2200505 4500008004100000022001400041245018900055210006900244260001300313300001000326490000700336520107200343653002801415653001001443653000901453653002201462653001101484653003801495653001101533653003001544653004401574653004301618653001601661653001101677653001701688653005001705653001401755653000901769653001601778653002001794653001401814653003201828653002801860653000901888653001901897653002101916100003001937700001901967700002001986700002002006700002902026700002002055700001702075856012902092 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 aCutaneous 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.
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 uhttps://www.clinbioinfosspa.es/content/role-cpi-17-restoring-skin-homoeostasis-cutaneous-field-cancerization-effects-topical02491nas a2200373 4500008004100000022001400041245014600055210006900201260001600270300000800286490000600294520125600300653001101556653003801567653003401605653001301639653002501652653001101677653000901688100002701697700001701724700002701741700002001768700002301788700002401811700002001835700002001855700002801875700002001903700002501923700002001948700001901968856013001987 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 aFinding 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.
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 uhttps://www.clinbioinfosspa.es/content/four-new-loci-associations-discovered-pathway-based-and-network-analyses-genome-wide-003322nas a2200613 4500008004100000022001400041245010400055210006900159260001600228300001100244490000700255520144400262653001901706653001201725653001501737653002801752653002501780653001701805653002501822653002001847653002001867653002501887653002201912653003001934653003101964653001101995653000902006653002602015653003602041653001102077653002702088653000902115653001502124653004102139100002302180700001602203700001902219700003002238700002702268700002102295700002002316700002002336700001702356700002002373700002702393700002202420700001802442700002902460700001802489700002002507700002202527700002302549856013602572 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 aEarly 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.
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 uhttps://www.clinbioinfosspa.es/content/hypoxia-promotes-efficient-differentiation-human-embryonic-stem-cells-functional-endothelium03045nas a2200565 4500008004100000022001400041245009600055210006900151260001300220300001400233490000700247520132400254653002401578653001201602653002501614653002801639653002401667653002501691653001701716653001101733653002101744653002201765653001101787653000901798653002801807653001301835653001301848653003601861653003201897653002501929653001001954653003301964100002201997700001902019700002602038700003302064700002002097700001802117700002302135700002202158700001802180700002402198700001902222700002102241700002202262700002002284700002702304700002502331856012302356 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 aRetinitis 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.
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 uhttps://www.clinbioinfosspa.es/content/mutation-spectrum-eys-spanish-patients-autosomal-recessive-retinitis-pigmentosa03272nas a2200517 4500008004100000022001400041245013100055210006900186260001600255300001200271490000700283520168900290653001201979653001501991653001002006653000902016653002202025653001402047653002502061653002502086653001102111653003002122653004302152653001102195653000902206653001602215653004402231653001402275653005202289653001802341653002402359653002202383100002102405700002502426700001302451700001502464700002902479700001702508700001602525700002002541700001402561700001602575700001502591700001602606856013202622 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 aUndifferentiated 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.
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 uhttps://www.clinbioinfosspa.es/content/molecular-profiling-related-poor-prognosis-thyroid-carcinoma-combining-gene-expression-002990nas a2200421 4500008004100000022001400041245007000055210006800125260001600193300000800209490000600217520169900223653003601922653003001958653004301988653001102031653000902042653002302051653002002074653002402094653002202118653001402140653002402154653003202178653001902210653002402229653002002253100002202273700002402295700002002319700002502339700001602364700001702380700002202397700002002419700002602439856010302465 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 aBACKGROUND: 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.
RESULTS: 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.
CONCLUSION: 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.
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 uhttps://www.clinbioinfosspa.es/content/evidence-systems-level-molecular-mechanisms-tumorigenesis-0