@article {807, title = {HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS): A Spanish Group for Research on Sarcomas (GEIS) study.}, journal = {Cell Mol Life Sci}, volume = {81}, year = {2024}, month = {2024 May 17}, pages = {219}, abstract = {

HMGA1 is a structural epigenetic chromatin factor that has been associated with tumor progression and drug resistance. Here, we reported the prognostic/predictive value of HMGA1 for trabectedin in advanced soft-tissue sarcoma (STS) and the effect of inhibiting HMGA1 or the mTOR downstream pathway in trabectedin activity. The prognostic/predictive value of HMGA1 expression was assessed in a cohort of 301 STS patients at mRNA (n = 133) and protein level (n = 272), by HTG EdgeSeq transcriptomics and immunohistochemistry, respectively. The effect of HMGA1 silencing on trabectedin activity and gene expression profiling was measured in leiomyosarcoma cells. The effect of combining mTOR inhibitors with trabectedin was assessed on cell viability in vitro studies, whereas in vivo studies tested the activity of this combination. HMGA1 mRNA and protein expression were significantly associated with worse progression-free survival of trabectedin and worse overall survival in STS. HMGA1 silencing sensitized leiomyosarcoma cells for trabectedin treatment, reducing the spheroid area and increasing cell death. The downregulation of HGMA1 significantly decreased the enrichment of some specific gene sets, including the PI3K/AKT/mTOR pathway. The inhibition of mTOR, sensitized leiomyosarcoma cultures for trabectedin treatment, increasing cell death. In in vivo studies, the combination of rapamycin with trabectedin downregulated HMGA1 expression and stabilized tumor growth of 3-methylcholantrene-induced sarcoma-like models. HMGA1 is an adverse prognostic factor for trabectedin treatment in advanced STS. HMGA1 silencing increases trabectedin efficacy, in part by modulating the mTOR signaling pathway. Trabectedin plus mTOR inhibitors are active in preclinical models of sarcoma, downregulating HMGA1 expression levels and stabilizing tumor growth.

}, keywords = {Animals, Antineoplastic Agents, Alkylating, Cell Line, Tumor, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, HMGA1a Protein, Humans, Leiomyosarcoma, Mice, Prognosis, Sarcoma, Signal Transduction, TOR Serine-Threonine Kinases, Trabectedin, Xenograft Model Antitumor Assays}, issn = {1420-9071}, doi = {10.1007/s00018-024-05250-y}, author = {Moura, David S and Mondaza-Hernandez, Jose L and Sanchez-Bustos, Paloma and Pe{\~n}a-Chilet, Maria and Cordero-Varela, Juan A and Lopez-Alvarez, Maria and Carrillo-Garcia, Jaime and Martin-Ruiz, Marta and Romero-Gonzalez, Pablo and Renshaw-Calderon, Marta and Ramos, Rafael and Marcilla, David and Alvarez-Alegret, Ramiro and Agra-Pujol, Carolina and Izquierdo, Francisco and Ortega-Medina, Luis and Martin-Davila, Francisco and Hernandez-Leon, Carmen Nieves and Romagosa, Cleofe and Salgado, Maria Angeles Vaz and Lavernia, Javier and Bagu{\'e}, Silvia and Mayodormo-Aranda, Empar and Alvarez, Rosa and Valverde, Claudia and Martinez-Trufero, Javier and Castilla-Ramirez, Carolina and Gutierrez, Antonio and Dopazo, Joaquin and Hindi, Nadia and Garcia-Foncillas, Jesus and Martin-Broto, Javier} } @article {813, title = {The integrated genomic surveillance system of Andalusia (SIEGA) provides a One Health regional resource connected with the clinic.}, journal = {Sci Rep}, volume = {14}, year = {2024}, month = {2024 Aug 19}, pages = {19200}, abstract = {

The One Health approach, recognizing the interconnectedness of human, animal, and environmental health, has gained significance amid emerging zoonotic diseases and antibiotic resistance concerns. This paper aims to demonstrate the utility of a collaborative tool, the SIEGA, for monitoring infectious diseases across domains, fostering a comprehensive understanding of disease dynamics and risk factors, highlighting the pivotal role of One Health surveillance systems. Raw whole-genome sequencing is processed through different species-specific open software that additionally reports the presence of genes associated to anti-microbial resistances and virulence. The SIEGA application is a Laboratory Information Management System, that allows customizing reports, detect transmission chains, and promptly alert on alarming genetic similarities. The SIEGA initiative has successfully accumulated a comprehensive collection of more than 1900 bacterial genomes, including Salmonella enterica, Listeria monocytogenes, Campylobacter jejuni, Escherichia coli, Yersinia enterocolitica and Legionella pneumophila, showcasing its potential in monitoring pathogen transmission, resistance patterns, and virulence factors. SIEGA enables customizable reports and prompt detection of transmission chains, highlighting its contribution to enhancing vigilance and response capabilities. Here we show the potential of genomics in One Health surveillance when supported by an appropriate bioinformatic tool. By facilitating precise disease control strategies and antimicrobial resistance management, SIEGA enhances global health security and reduces the burden of infectious diseases. The integration of health data from humans, animals, and the environment, coupled with advanced genomics, underscores the importance of a holistic One Health approach in mitigating health threats.

}, keywords = {Animals, Drug Resistance, Bacterial, Genome, Bacterial, Genomics, Humans, One Health, Virulence Factors, Whole Genome Sequencing}, issn = {2045-2322}, doi = {10.1038/s41598-024-70107-0}, author = {Casimiro-Soriguer, Carlos S and Perez-Florido, Javier and Robles, Enrique A and Lara, Mar{\'\i}a and Aguado, Andrea and Rodr{\'\i}guez Iglesias, Manuel A and Lepe, Jose A and Garc{\'\i}a, Federico and P{\'e}rez-Alegre, M{\'o}nica and And{\'u}jar, Elo{\'\i}sa and Jim{\'e}nez, Victoria E and Camino, Lola P and Loruso, Nicola and Ameyugo, Ulises and Vazquez, Isabel Mar{\'\i}a and Lozano, Carlota M and Chaves, J Alberto and Dopazo, Joaquin} } @article {775, title = {microRNAs-mediated regulation of insulin signaling in white adipose tissue during aging: Role of caloric restriction.}, journal = {Aging Cell}, year = {2023}, month = {2023 Jul 04}, pages = {e13919}, abstract = {

Caloric restriction is a non-pharmacological intervention known to ameliorate the metabolic defects associated with aging, including insulin resistance. The levels of miRNA expression may represent a predictive tool for aging-related alterations. In order to investigate the role of miRNAs underlying insulin resistance in adipose tissue during the early stages of aging, 3- and 12-month-old male animals fed ad libitum, and 12-month-old male animals fed with a 20\% caloric restricted diet were used. In this work we demonstrate that specific miRNAs may contribute to the impaired insulin-stimulated glucose metabolism specifically in the subcutaneous white adipose tissue, through the regulation of target genes implicated in the insulin signaling cascade. Moreover, the expression of these miRNAs is modified by caloric restriction in middle-aged animals, in accordance with the improvement of the metabolic state. Overall, our work demonstrates that alterations in posttranscriptional gene expression because of miRNAs dysregulation might represent an endogenous mechanism by which insulin response in the subcutaneous fat depot is already affected at middle age. Importantly, caloric restriction could prevent this modulation, demonstrating that certain miRNAs could constitute potential biomarkers of age-related metabolic alterations.

}, issn = {1474-9726}, doi = {10.1111/acel.13919}, author = {Corrales, Patricia and Martin-Taboada, Marina and Vivas-Garc{\'\i}a, Yurena and Torres, Lucia and Ramirez-Jimenez, Laura and Lopez, Yamila and Horrillo, Daniel and Vila-Bedmar, Rocio and Barber-Cano, Eloisa and Izquierdo-Lahuerta, Adriana and Pe{\~n}a-Chilet, Maria and Mart{\'\i}nez, Carmen and Dopazo, Joaquin and Ros, Manuel and Medina-Gomez, Gema} } @article {754, title = {Incidence and Prevalence of Children{\textquoteright}s Diffuse Lung Disease in Spain.}, journal = {Arch Bronconeumol}, volume = {58}, year = {2022}, month = {2022 Jan}, pages = {22-29}, abstract = {

BACKGROUND: Children{\textquoteright}s diffuse lung disease, also known as children{\textquoteright}s Interstitial Lung Diseases (chILD), are a heterogeneous group of rare diseases with relevant morbidity and mortality, which diagnosis and classification are very complex. Epidemiological data are scarce. The aim of this study was to analyse incidence and prevalence of chILD in Spain.

METHODS: Multicentre observational prospective study in patients from 0 to 18 years of age with chILD to analyse its incidence and prevalence in Spain, based on data reported in 2018 and 2019.

RESULTS: A total of 381 cases with chILD were notified from 51 paediatric pulmonology units all over Spain, covering the 91.7\% of the paediatric population. The average incidence of chILD was 8.18 (CI 95\% 6.28-10.48) new cases/million of children per year. The average prevalence of chILD was 46.53 (CI 95\% 41.81-51.62) cases/million of children. The age group with the highest prevalence were children under 1 year of age. Different types of disorders were seen in children 2-18 years of age compared with children 0-2 years of age. Most frequent cases were: primary pulmonary interstitial glycogenosis in neonates (17/65), neuroendocrine cell hyperplasia of infancy in infants from 1 to 12 months (44/144), idiopathic pulmonary haemosiderosis in children from 1 to 5 years old (13/74), hypersensitivity pneumonitis in children from 5 to 10 years old (9/51), and scleroderma in older than 10 years old (8/47).

CONCLUSIONS: We found a higher incidence and prevalence of chILD than previously described probably due to greater understanding and increased clinician awareness of these rare diseases.

}, issn = {1579-2129}, doi = {10.1016/j.arbres.2021.06.001}, author = {Torrent-Vernetta, Alba and Gaboli, Mirella and Castillo-Corull{\'o}n, Silvia and Mond{\'e}jar-L{\'o}pez, Pedro and Sanz Santiago, Ver{\'o}nica and Costa-Colomer, Jordi and Osona, Borja and Torres-Borrego, Javier and de la Serna-Bl{\'a}zquez, Olga and Bell{\'o}n Alonso, Sara and Caro Aguilera, Pilar and Gimeno-D{\'\i}az de Atauri, {\'A}lvaro and Valenzuela Soria, Alfredo and Ayats, Roser and Martin de Vicente, Carlos and Velasco Gonz{\'a}lez, Valle and Moure Gonz{\'a}lez, Jos{\'e} Domingo and Canino Calder{\'\i}n, Elisa Mar{\'\i}a and Pastor-Vivero, Mar{\'\i}a Dolores and Villar {\'A}lvarez, Mar{\'\i}a {\'A}ngeles and Rovira-Amigo, Sandra and Iglesias Serrano, Ignacio and D{\'\i}ez Izquierdo, Ana and de Mir Messa, In{\'e}s and Gartner, Silvia and Navarro, Alexandra and Baz-Red{\'o}n, Noelia and Carmona, Rosario and Camats-Tarruella, N{\'u}ria and Fern{\'a}ndez-Cancio, M{\'o}nica and Rapp, Christina and Dopazo, Joaquin and Griese, Matthias and Moreno-Gald{\'o}, Antonio} } @article {736, title = {COVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms.}, journal = {Mol Syst Biol}, volume = {17}, year = {2021}, month = {2021 10}, pages = {e10387}, abstract = {

We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.

}, keywords = {Antiviral Agents, Computational Biology, Computer Graphics, COVID-19, Cytokines, Data Mining, Databases, Factual, Gene Expression Regulation, Host Microbial Interactions, Humans, Immunity, Cellular, Immunity, Humoral, Immunity, Innate, Lymphocytes, Metabolic Networks and Pathways, Myeloid Cells, Protein Interaction Mapping, SARS-CoV-2, Signal Transduction, Software, Transcription Factors, Viral Proteins}, issn = {1744-4292}, doi = {10.15252/msb.202110387}, author = {Ostaszewski, Marek and Niarakis, Anna and Mazein, Alexander and Kuperstein, Inna and Phair, Robert and Orta-Resendiz, Aurelio and Singh, Vidisha and Aghamiri, Sara Sadat and Acencio, Marcio Luis and Glaab, Enrico and Ruepp, Andreas and Fobo, Gisela and Montrone, Corinna and Brauner, Barbara and Frishman, Goar and Monraz G{\'o}mez, Luis Crist{\'o}bal and Somers, Julia and Hoch, Matti and Kumar Gupta, Shailendra and Scheel, Julia and Borlinghaus, Hanna and Czauderna, Tobias and Schreiber, Falk and Montagud, Arnau and Ponce de Leon, Miguel and Funahashi, Akira and Hiki, Yusuke and Hiroi, Noriko and Yamada, Takahiro G and Dr{\"a}ger, Andreas and Renz, Alina and Naveez, Muhammad and Bocskei, Zsolt and Messina, Francesco and B{\"o}rnigen, Daniela and Fergusson, Liam and Conti, Marta and Rameil, Marius and Nakonecnij, Vanessa and Vanhoefer, Jakob and Schmiester, Leonard and Wang, Muying and Ackerman, Emily E and Shoemaker, Jason E and Zucker, Jeremy and Oxford, Kristie and Teuton, Jeremy and Kocakaya, Ebru and Summak, G{\"o}k{\c c}e Ya{\u g}mur and Hanspers, Kristina and Kutmon, Martina and Coort, Susan and Eijssen, Lars and Ehrhart, Friederike and Rex, Devasahayam Arokia Balaya and Slenter, Denise and Martens, Marvin and Pham, Nhung and Haw, Robin and Jassal, Bijay and Matthews, Lisa and Orlic-Milacic, Marija and Senff Ribeiro, Andrea and Rothfels, Karen and Shamovsky, Veronica and Stephan, Ralf and Sevilla, Cristoffer and Varusai, Thawfeek and Ravel, Jean-Marie and Fraser, Rupsha and Ortseifen, Vera and Marchesi, Silvia and Gawron, Piotr and Smula, Ewa and Heirendt, Laurent and Satagopam, Venkata and Wu, Guanming and Riutta, Anders and Golebiewski, Martin and Owen, Stuart and Goble, Carole and Hu, Xiaoming and Overall, Rupert W and Maier, Dieter and Bauch, Angela and Gyori, Benjamin M and Bachman, John A and Vega, Carlos and Grou{\`e}s, Valentin and Vazquez, Miguel and Porras, Pablo and Licata, Luana and Iannuccelli, Marta and Sacco, Francesca and Nesterova, Anastasia and Yuryev, Anton and de Waard, Anita and Turei, Denes and Luna, Augustin and Babur, Ozgun and Soliman, Sylvain and Valdeolivas, Alberto and Esteban-Medina, Marina and Pe{\~n}a-Chilet, Maria and Rian, Kinza and Helikar, Tom{\'a}{\v s} and Puniya, Bhanwar Lal and Modos, Dezso and Treveil, Agatha and Olbei, Marton and De Meulder, Bertrand and Ballereau, Stephane and Dugourd, Aur{\'e}lien and Naldi, Aur{\'e}lien and No{\"e}l, Vincent and Calzone, Laurence and Sander, Chris and Demir, Emek and Korcsmaros, Tamas and Freeman, Tom C and Aug{\'e}, Franck and Beckmann, Jacques S and Hasenauer, Jan and Wolkenhauer, Olaf and Wilighagen, Egon L and Pico, Alexander R and Evelo, Chris T and Gillespie, Marc E and Stein, Lincoln D and Hermjakob, Henning and D{\textquoteright}Eustachio, Peter and Saez-Rodriguez, Julio and Dopazo, Joaquin and Valencia, Alfonso and Kitano, Hiroaki and Barillot, Emmanuel and Auffray, Charles and Balling, Rudi and Schneider, Reinhard} } @article {731, title = {De novo small deletion affecting transcription start site of short isoform of AUTS2 gene in a patient with syndromic neurodevelopmental defects.}, journal = {Am J Med Genet A}, volume = {185}, year = {2021}, month = {2021 03}, pages = {877-883}, abstract = {

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.

}, keywords = {Child, Preschool, Cytoskeletal Proteins, Dwarfism, Exons, Gene Expression Regulation, Genetic Association Studies, Humans, Male, Neurodevelopmental Disorders, Protein Isoforms, RNA, Messenger, Sequence Deletion, Syndrome, Transcription Factors, Transcription Initiation Site, Transcription, Genetic}, issn = {1552-4833}, doi = {10.1002/ajmg.a.62017}, author = {Martinez-Delgado, Beatriz and Lopez-Martin, Estrella and Lara-Herguedas, Juli{\'a}n and Monzon, Sara and Cuesta, Isabel and Juli{\'a}, Miguel and Aquino, Virginia and Rodriguez-Martin, Carlos and Damian, Alejandra and Gonzalo, Irene and Gomez-Mariano, Gema and Baladron, Beatriz and Cazorla, Rosario and Iglesias, Gema and Roman, Enriqueta and Ros, Purificacion and Tutor, Pablo and Mellor, Susana and Jimenez, Carlos and Cabrejas, Maria Jose and Gonzalez-Vioque, Emiliano and Alonso, Javier and Bermejo-S{\'a}nchez, Eva and Posada, Manuel} } @article {720, title = {A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin.}, journal = {Mol Oncol}, volume = {15}, year = {2021}, month = {2021 12}, pages = {3691-3705}, abstract = {

Predictive biomarkers of trabectedin represent an unmet need in advanced soft-tissue sarcomas (STS). DNA damage repair (DDR) genes, involved in homologous recombination or nucleotide excision repair, had been previously described as biomarkers of trabectedin resistance or sensitivity, respectively. The majority of these studies only focused on specific factors (ERCC1, ERCC5, and BRCA1) and did not evaluate several other DDR-related genes that could have a relevant role for trabectedin efficacy. In this retrospective translational study, 118 genes involved in DDR were evaluated to determine, by transcriptomics, a predictive gene signature of trabectedin efficacy. A six-gene predictive signature of trabectedin efficacy was built in a series of 139 tumor samples from patients with advanced STS. Patients in the high-risk gene signature group showed a significantly worse progression-free survival compared with patients in the low-risk group (2.1 vs 6.0 months, respectively). Differential gene expression analysis defined new potential predictive biomarkers of trabectedin sensitivity (PARP3 and CCNH) or resistance (DNAJB11 and PARP1). Our study identified a new gene signature that significantly predicts patients with higher probability to respond to treatment with trabectedin. Targeting some genes of this signature emerges as a potential strategy to enhance trabectedin efficacy.

}, issn = {1878-0261}, doi = {10.1002/1878-0261.12996}, author = {Moura, David S and Pe{\~n}a-Chilet, Maria and Cordero Varela, Juan Antonio and Alvarez-Alegret, Ramiro and Agra-Pujol, Carolina and Izquierdo, Francisco and Ramos, Rafael and Ortega-Medina, Luis and Martin-Davila, Francisco and Castilla-Ramirez, Carolina and Hernandez-Leon, Carmen Nieves and Romagosa, Cleofe and Vaz Salgado, Maria Angeles and Lavernia, Javier and Bagu{\'e}, Silvia and Mayodormo-Aranda, Empar and Vicioso, Luis and Hern{\'a}ndez Barcel{\'o}, Jose Emilio and Rubio-Casadevall, Jordi and de Juan, Ana and Fia{\~n}o-Valverde, Maria Concepcion and Hindi, Nadia and Lopez-Alvarez, Maria and Lacerenza, Serena and Dopazo, Joaquin and Gutierrez, Antonio and Alvarez, Rosa and Valverde, Claudia and Martinez-Trufero, Javier and Martin-Broto, Javier} } @article {714, title = {The NCI Genomic Data Commons}, journal = {Nature Genetics}, year = {2021}, month = {Oct-02-2022}, issn = {1061-4036}, doi = {10.1038/s41588-021-00791-5}, url = {http://www.nature.com/articles/s41588-021-00791-5}, author = {Heath, Allison P. and Ferretti, Vincent and Agrawal, Stuti and An, Maksim and Angelakos, James C. and Arya, Renuka and Bajari, Rosita and Baqar, Bilal and Barnowski, Justin H. B. and Burt, Jeffrey and Catton, Ann and Chan, Brandon F. and Chu, Fay and Cullion, Kim and Davidsen, Tanja and Do, Phuong-My and Dompierre, Christian and Ferguson, Martin L. and Fitzsimons, Michael S. and Ford, Michael and Fukuma, Miyuki and Gaheen, Sharon and Ganji, Gajanan L. and Garcia, Tzintzuni I. and George, Sameera S. and Gerhard, Daniela S. and Gerthoffert, Francois and Gomez, Fauzi and Han, Kang and Hernandez, Kyle M. and Issac, Biju and Jackson, Richard and Jensen, Mark A. and Joshi, Sid and Kadam, Ajinkya and Khurana, Aishmit and Kim, Kyle M. J. and Kraft, Victoria E. and Li, Shenglai and Lichtenberg, Tara M. and Lodato, Janice and Lolla, Laxmi and Martinov, Plamen and Mazzone, Jeffrey A. and Miller, Daniel P. and Miller, Ian and Miller, Joshua S. and Miyauchi, Koji and Murphy, Mark W. and Nullet, Thomas and Ogwara, Rowland O. and Ortu{\~n}o, Francisco M. and Pedrosa, Jes{\'u}s and Pham, Phuong L. and Popov, Maxim Y. and Porter, James J. and Powell, Raymond and Rademacher, Karl and Reid, Colin P. and Rich, Samantha and Rogel, Bessie and Sahni, Himanso and Savage, Jeremiah H. and Schmitt, Kyle A. and Simmons, Trevar J. and Sislow, Joseph and Spring, Jonathan and Stein, Lincoln and Sullivan, Sean and Tang, Yajing and Thiagarajan, Mathangi and Troyer, Heather D. and Wang, Chang and Wang, Zhining and West, Bedford L. and Wilmer, Alex and Wilson, Shane and Wu, Kaman and Wysocki, William P. and Xiang, Linda and Yamada, Joseph T. and Yang, Liming and Yu, Christine and Yung, Christina K. and Zenklusen, Jean Claude and Zhang, Junjun and Zhang, Zhenyu and Zhao, Yuanheng and Zubair, Ariz and Staudt, Louis M. and Grossman, Robert L.} } @article {704, title = {Transparency and reproducibility in artificial intelligence.}, journal = {Nature}, volume = {586}, year = {2020}, month = {2020 10}, pages = {E14-E16}, keywords = {Algorithms, Artificial Intelligence, Reproducibility of Results}, issn = {1476-4687}, doi = {10.1038/s41586-020-2766-y}, author = {Haibe-Kains, Benjamin and Adam, George Alexandru and Hosny, Ahmed and Khodakarami, Farnoosh and Waldron, Levi and Wang, Bo and McIntosh, Chris and Goldenberg, Anna and Kundaje, Anshul and Greene, Casey S and Broderick, Tamara and Hoffman, Michael M and Leek, Jeffrey T and Korthauer, Keegan and Huber, Wolfgang and Brazma, Alvis and Pineau, Joelle and Tibshirani, Robert and Hastie, Trevor and Ioannidis, John P A and Quackenbush, John and Aerts, Hugo J W L} } @article {423, title = {Pazopanib for treatment of advanced malignant and dedifferentiated solitary fibrous tumour: a multicentre, single-arm, phase 2 trial.}, journal = {Lancet Oncol}, volume = {20}, year = {2019}, month = {2019 Jan}, pages = {134-144}, abstract = {

BACKGROUND: 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.

}, keywords = {Adult, Aged, Angiogenesis Inhibitors, Antineoplastic Agents, Female, Humans, Indazoles, Male, Middle Aged, Multivariate Analysis, Pyrimidines, Response Evaluation Criteria in Solid Tumors, Soft Tissue Neoplasms, Solitary Fibrous Tumors, Sulfonamides, Survival Analysis}, issn = {1474-5488}, doi = {10.1016/S1470-2045(18)30676-4}, author = {Martin-Broto, Javier and Stacchiotti, Silvia and Lopez-Pousa, Antonio and Redondo, Andres and Bernabeu, Daniel and de Alava, Enrique and Casali, Paolo G and Italiano, Antoine and Gutierrez, Antonio and Moura, David S and Pe{\~n}a-Chilet, Maria and Diaz-Martin, Juan and Biscuola, Michele and Taron, Miguel and Collini, Paola and Ranchere-Vince, Dominique and Garcia Del Muro, Xavier and Grignani, Giovanni and Dumont, Sarah and Martinez-Trufero, Javier and Palmerini, Emanuela and Hindi, Nadia and Sebio, Ana and Dopazo, Joaquin and Dei Tos, Angelo Paolo and LeCesne, Axel and Blay, Jean-Yves and Cruz, Josefina} } @article {398, title = {Genomics of the origin and evolution of Citrus.}, journal = {Nature}, volume = {554}, year = {2018}, month = {2018 Feb 15}, pages = {311-316}, abstract = {

The genus Citrus, comprising some of the most widely cultivated fruit crops worldwide, includes an uncertain number of species. Here we describe ten natural citrus species, using genomic, phylogenetic and biogeographic analyses of 60 accessions representing diverse citrus germ plasms, and propose that citrus diversified during the late Miocene epoch through a rapid southeast Asian radiation that correlates with a marked weakening of the monsoons. A second radiation enabled by migration across the Wallace line gave rise to the Australian limes in the early Pliocene epoch. Further identification and analyses of hybrids and admixed genomes provides insights into the genealogy of major commercial cultivars of citrus. Among mandarins and sweet orange, we find an extensive network of relatedness that illuminates the domestication of these groups. Widespread pummelo admixture among these mandarins and its correlation with fruit size and acidity suggests a plausible role of pummelo introgression in the selection of palatable mandarins. This work provides a new evolutionary framework for the genus Citrus.

}, keywords = {Asia, Southeastern, Biodiversity, citrus, Crop Production, Evolution, Molecular, Genetic Speciation, Genome, Plant, Genomics, Haplotypes, Heterozygote, History, Ancient, Human Migration, Hybridization, Genetic, Phylogeny}, issn = {1476-4687}, doi = {10.1038/nature25447}, author = {Wu, Guohong Albert and Terol, Javier and Iba{\~n}ez, Victoria and L{\'o}pez-Garc{\'\i}a, Antonio and P{\'e}rez-Rom{\'a}n, Estela and Borred{\'a}, Carles and Domingo, Concha and Tadeo, Francisco R and Carbonell-Caballero, Jos{\'e} and Alonso, Roberto and Curk, Franck and Du, Dongliang and Ollitrault, Patrick and Roose, Mikeal L and Dopazo, Joaquin and Gmitter, Frederick G and Rokhsar, Daniel S and Talon, Manuel} } @article {407, title = {The modular network structure of the mutational landscape of Acute Myeloid Leukemia.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0202926}, abstract = {

Acute myeloid leukemia (AML) is associated with the sequential accumulation of acquired genetic alterations. Although at diagnosis cytogenetic alterations are frequent in AML, roughly 50\% of patients present an apparently normal karyotype (NK), leading to a highly heterogeneous prognosis. Due to this significant heterogeneity, it has been suggested that different molecular mechanisms may trigger the disease with diverse prognostic implications. We performed whole-exome sequencing (WES) of tumor-normal matched samples of de novo AML-NK patients lacking mutations in NPM1, CEBPA or FLT3-ITD to identify new gene mutations with potential prognostic and therapeutic relevance to patients with AML. Novel candidate-genes, together with others previously described, were targeted resequenced in an independent cohort of 100 de novo AML patients classified in the cytogenetic intermediate-risk (IR) category. A mean of 4.89 mutations per sample were detected in 73 genes, 35 of which were mutated in more than one patient. After a network enrichment analysis, we defined a single in silico model and established a set of seed-genes that may trigger leukemogenesis in patients with normal karyotype. The high heterogeneity of gene mutations observed in AML patients suggested that a specific alteration could not be as essential as the interaction of deregulated pathways.

}, keywords = {Adult, Aged, Cytodiagnosis, Exome Sequencing, Female, Gene Regulatory Networks, Genetic Association Studies, Genetic Heterogeneity, Humans, Karyotype, Leukemia, Myeloid, Acute, Male, Middle Aged, mutation, Neoplasm Proteins, Nucleophosmin, Prognosis}, issn = {1932-6203}, doi = {10.1371/journal.pone.0202926}, author = {Ib{\'a}{\~n}ez, Mariam and Carbonell-Caballero, Jos{\'e} and Such, Esperanza and Garc{\'\i}a-Alonso, Luz and Liquori, Alessandro and L{\'o}pez-Pav{\'\i}a, Mar{\'\i}a and LLop, Marta and Alonso, Carmen and Barrag{\'a}n, Eva and G{\'o}mez-Segu{\'\i}, In{\'e}s and Neef, Alexander and Herv{\'a}s, David and Montesinos, Pau and Sanz, Guillermo and Sanz, Miguel Angel and Dopazo, Joaquin and Cervera, Jos{\'e}} } @article {453, title = {The Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations.}, journal = {PLoS One}, volume = {11}, year = {2016}, month = {2016}, pages = {e0148346}, abstract = {

Preliminary Acute Promyelocytic Leukemia (APL) whole exome sequencing (WES) studies have identified a huge number of somatic mutations affecting more than a hundred different genes mainly in a non-recurrent manner, suggesting that APL is a heterogeneous disease with secondary relevant changes not yet defined. To extend our knowledge of subtle genetic alterations involved in APL that might cooperate with PML/RARA in the leukemogenic process, we performed a comprehensive analysis of somatic mutations in APL combining WES with sequencing of a custom panel of targeted genes by next-generation sequencing. To select a reduced subset of high confidence candidate driver genes, further in silico analysis were carried out. After prioritization and network analysis we found recurrent deleterious mutations in 8 individual genes (STAG2, U2AF1, SMC1A, USP9X, IKZF1, LYN, MYCBP2 and PTPN11) with a strong potential of being involved in APL pathogenesis. Our network analysis of multiple mutations provides a reliable approach to prioritize genes for additional analysis, improving our knowledge of the leukemogenesis interactome. Additionally, we have defined a functional module in the interactome of APL. The hypothesis is that the number, or the specific combinations, of mutations harbored in each patient might not be as important as the disturbance caused in biological key functions, triggered by several not necessarily recurrent mutations.

}, keywords = {Exome, Gene Regulatory Networks, Genome, Human, Humans, INDEL Mutation, Leukemia, Promyelocytic, Acute, mutation, Mutation Rate, Polymorphism, Single Nucleotide, Reproducibility of Results}, issn = {1932-6203}, doi = {10.1371/journal.pone.0148346}, author = {Ib{\'a}{\~n}ez, Mariam and Carbonell-Caballero, Jos{\'e} and Garc{\'\i}a-Alonso, Luz and Such, Esperanza and Jim{\'e}nez-Almaz{\'a}n, Jorge and Vidal, Enrique and Barrag{\'a}n, Eva and L{\'o}pez-Pav{\'\i}a, Mar{\'\i}a and LLop, Marta and Mart{\'\i}n, Iv{\'a}n and G{\'o}mez-Segu{\'\i}, In{\'e}s and Montesinos, Pau and Sanz, Miguel A and Dopazo, Joaquin and Cervera, Jos{\'e}} } @article {448, title = {Differential Features Between Chronic Skin Inflammatory Diseases Revealed in Skin-Humanized Psoriasis and Atopic Dermatitis Mouse Models.}, journal = {J Invest Dermatol}, year = {2015}, month = {2015 Sep 23}, abstract = {

Psoriasis (PS) and atopic dermatitis (AD) are chronic and relapsing inflammatory diseases of the skin affecting a large number of patients worldwide. Psoriasis is characterized by a Th1/Th17 immunological response whereas acute AD lesions exhibit Th2-dominant inflammation. Current single gene and signaling pathways-based models of inflammatory skin diseases are incomplete. Previous work allowed us to model psoriasis in skin-humanized mice through proper combinations of inflammatory cell components and disruption of barrier function. Herein we describe and characterize an animal model for AD using similar bioengineered-based approaches, by intradermal injection of human Th2 lymphocytes in regenerated human skin after partial removal of stratum corneum. In the present work we have extensively compared this model with the previous and an improved version of the PS model, in which Th17/Th1 lymphocytes replace exogenous cytokines. Comparative expression analyses revealed marked differences in specific epidermal proliferation and differentiation markers and immune-related molecules including antimicrobial peptides. Likewise, the composition of the dermal inflammatory infiltrate presented important differences. Availability of accurate and reliable animal models for these diseases will contribute to the understanding of the pathogenesis and provide valuable tools for drug development and testing.Journal of Investigative Dermatology accepted article preview online, 23 September 2015. doi:10.1038/jid.2015.362.

}, issn = {1523-1747}, doi = {10.1038/jid.2015.362}, author = {Carretero, M and Guerrero-Aspizua, S and Illera, N and Galvez, V and Navarro, M and Garc{\'\i}a-Garc{\'\i}a, F and Dopazo, J and Jorcano, J L and Larcher, F and Del Rio, M} } @article {1115, title = {Involvement of a citrus meiotic recombination TTC-repeat motif in the formation of gross deletions generated by ionizing radiation and MULE activation.}, journal = {BMC genomics}, volume = {16}, year = {2015}, month = {2015 Feb 13}, pages = {69}, abstract = {BACKGROUND: Transposable-element mediated chromosomal rearrangements require the involvement of two transposons and two double-strand breaks (DSB) located in close proximity. In radiobiology, DSB proximity is also a major factor contributing to rearrangements. However, the whole issue of DSB proximity remains virtually unexplored. RESULTS: Based on DNA sequencing analysis we show that the genomes of 2 derived mutations, Arrufatina (sport) and Nero (irradiation), share a similar 2 Mb deletion of chromosome 3. A 7 kb Mutator-like element found in Clemenules was present in Arrufatina in inverted orientation flanking the 5{\textquoteright} end of the deletion. The Arrufatina Mule displayed "dissimilar" 9-bp target site duplications separated by 2 Mb. Fine-scale single nucleotide variant analyses of the deleted fragments identified a TTC-repeat sequence motif located in the center of the deletion responsible of a meiotic crossover detected in the citrus reference genome. CONCLUSIONS: Taken together, this information is compatible with the proposal that in both mutants, the TTC-repeat motif formed a triplex DNA structure generating a loop that brought in close proximity the originally distinct reactive ends. In Arrufatina, the loop brought the Mule ends nearby the 2 distinct insertion target sites and the inverted insertion of the transposable element between these target sites provoked the release of the in-between fragment. This proposal requires the involvement of a unique transposon and sheds light on the unresolved question of how two distinct sites become located in close proximity. These observations confer a crucial role to the TTC-repeats in fundamental plant processes as meiotic recombination and chromosomal rearrangements.}, issn = {1471-2164}, doi = {10.1186/s12864-015-1280-3}, url = {http://www.biomedcentral.com/1471-2164/16/69}, author = {Terol, Javier and Iba{\~n}ez, Victoria and Carbonell, Jos{\'e} and Alonso, Roberto and Estornell, Leandro H and Licciardello, Concetta and Gut, Ivo G and Joaqu{\'\i}n Dopazo and Talon, Manuel} } @article {563, title = {Involvement of a citrus meiotic recombination TTC-repeat motif in the formation of gross deletions generated by ionizing radiation and MULE activation}, journal = {BMC Genomics}, volume = {16}, year = {2015}, month = {Feb}, pages = {69}, abstract = {Transposable-element mediated chromosomal rearrangements require the involvement of two transposons and two double-strand breaks (DSB) located in close proximity. In radiobiology, DSB proximity is also a major factor contributing to rearrangements. However, the whole issue of DSB proximity remains virtually unexplored.}, issn = {1471-2164}, doi = {10.1186/s12864-015-1280-3}, url = {https://doi.org/10.1186/s12864-015-1280-3}, author = {Terol, Javier and Iba{\~n}ez, Victoria and Carbonell, Jos{\'e} and Alonso, Roberto and Estornell, Leandro H. and Licciardello, Concetta and Gut, Ivo G. and Dopazo, Joaquin and Talon, Manuel} } @article {1121, title = {A phylogenetic analysis of 34 chloroplast genomes elucidates the relationships between wild and domestic species within the genus Citrus.}, journal = {Molecular biology and evolution}, volume = {32}, number = {8}, year = {2015}, month = {2015 Apr 14}, pages = {2015-2035}, abstract = {Citrus genus includes some of the most important cultivated fruit trees worldwide. Despite being extensively studied because of its commercial relevance, the origin of cultivated citrus species and the history of its domestication still remain an open question. Here we present a phylogenetic analysis of the chloroplast genomes of 34 citrus genotypes which constitutes the most comprehensive and detailed study to date on the evolution and variability of the genus Citrus. A statistical model was used to estimate divergence times between the major citrus groups. Additionally, a complete map of the variability across the genome of different citrus species was produced, including single nucleotide variants, heteroplasmic positions, indels and large structural variants. The distribution of all these variants provided further independent support to the phylogeny obtained. An unexpected finding was the high level of heteroplasmy found in several of the analysed genomes. The use of the complete chloroplast DNA not only paves the way for a better understanding of the phylogenetic relationships within the Citrus genus, but also provides original insights into other elusive evolutionary processes such as chloroplast inheritance, heteroplasmy and gene selection.}, keywords = {chloroplast, citrus, Phylogeny, WGS}, issn = {1537-1719}, doi = {10.1093/molbev/msv082}, url = {http://mbe.oxfordjournals.org/content/early/2015/04/27/molbev.msv082.full}, author = {Carbonell-Caballero, Jos{\'e} and Alonso, Roberto and Iba{\~n}ez, Victoria and Terol, Javier and Talon, Manuel and Dopazo, Joaquin} } @article {493, title = {The Activation of the Sox2 RR2 Pluripotency Transcriptional Reporter in Human Breast Cancer Cell Lines is Dynamic and Labels Cells with Higher Tumorigenic Potential.}, journal = {Front Oncol}, volume = {4}, year = {2014}, month = {2014}, pages = {308}, abstract = {

The striking similarity displayed at the mechanistic level between tumorigenesis and the generation of induced pluripotent stem cells and the fact that genes and pathways relevant for embryonic development are reactivated during tumor progression highlights the link between pluripotency and cancer. Based on these observations, we tested whether it is possible to use a pluripotency-associated transcriptional reporter, whose activation is driven by the SRR2 enhancer from the Sox2 gene promoter (named S4+ reporter), to isolate cancer stem cells (CSCs) from breast cancer cell lines. The S4+ pluripotency transcriptional reporter allows the isolation of cells with enhanced tumorigenic potential and its activation was switched on and off in the cell lines studied, reflecting a plastic cellular process. Microarray analysis comparing the populations in which the reporter construct is active versus inactive showed that positive cells expressed higher mRNA levels of cytokines (IL-8, IL-6, TNF) and genes (such as ATF3, SNAI2, and KLF6) previously related with the CSC phenotype in breast cancer.

}, issn = {2234-943X}, doi = {10.3389/fonc.2014.00308}, author = {Iglesias, Juan Manuel and Leis, Olatz and P{\'e}rez Ruiz, Est{\'\i}baliz and Gumuzio Barrie, Juan and Garcia-Garcia, Francisco and Aduriz, Ariane and Beloqui, Izaskun and Hernandez-Garcia, Susana and Lopez-Mato, Maria Paz and Dopazo, Joaquin and Pandiella, Atanasio and Menendez, Javier A and Martin, Angel Garcia} } @article {1083, title = {A New Overgrowth Syndrome is Due to Mutations in RNF125.}, journal = {Human mutation}, volume = {35}, year = {2014}, month = {2014 Sep 5}, pages = {1436{\textendash}1441}, abstract = {Overgrowth syndromes (OGS) are a group of disorders in which all parameters of growth and physical development are above the mean for age and sex. We evaluated a series of 270 families from the Spanish Overgrowth Syndrome Registry with no known overgrowth syndrome. We identified one de novo deletion and three missense mutations in RNF125 in six patients from 4 families with overgrowth, macrocephaly, intellectual disability, mild hydrocephaly, hypoglycaemia and inflammatory diseases resembling Sj{\"o}gren syndrome. RNF125 encodes an E3 ubiquitin ligase and is a novel gene of OGS. Our studies of the RNF125 pathway point to upregulation of RIG-I-IPS1-MDA5 and/or disruption of the PI3K-AKT and interferon signaling pathways as the putative final effectors. This article is protected by copyright. All rights reserved.}, keywords = {NGS, prioritization, Rare Disease}, issn = {1098-1004}, doi = {10.1002/humu.22689}, url = {http://onlinelibrary.wiley.com/doi/10.1002/humu.22689/abstract}, author = {Tenorio, Jair and Mansilla, Alicia and Valencia, Mar{\'\i}a and Mart{\'\i}nez-Glez, V{\'\i}ctor and Romanelli, Valeria and Arias, Pedro and Castrej{\'o}n, Nerea and Poletta, Fernando and Guill{\'e}n-Navarro, Encarna and Gordo, Gema and Mansilla, Elena and Garc{\'\i}a-Santiago, F{\'e} and Gonz{\'a}lez-Casado, Isabel and Vallesp{\'\i}n, Elena and Palomares, Mar{\'\i}a and Mori, Mar{\'\i}a A and Santos-Simarro, Fernando and Garc{\'\i}a-Mi{\~n}aur, Sixto and Fern{\'a}ndez, Luis and Mena, Roc{\'\i}o and Benito-Sanz, Sara and Del Pozo, Angela and Silla, Juan Carlos and Iba{\~n}ez, Kristina and L{\'o}pez-Granados, Eduardo and Mart{\'\i}n-Trujillo, Alex and Montaner, David and Heath, Karen E and Campos-Barros, Angel and Joaqu{\'\i}n Dopazo and Nevado, Juli{\'a}n and Monk, David and Ruiz-P{\'e}rez, V{\'\i}ctor L and Lapunzina, Pablo} } @article {492, title = {Permanent cardiac sarcomere changes in a rabbit model of intrauterine growth restriction.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e113067}, abstract = {

BACKGROUND: Intrauterine growth restriction (IUGR) induces fetal cardiac remodelling and dysfunction, which persists postnatally and may explain the link between low birth weight and increased cardiovascular mortality in adulthood. However, the cellular and molecular bases for these changes are still not well understood. We tested the hypothesis that IUGR is associated with structural and functional gene expression changes in the fetal sarcomere cytoarchitecture, which remain present in adulthood.

METHODS AND RESULTS: IUGR was induced in New Zealand pregnant rabbits by selective ligation of the utero-placental vessels. Fetal echocardiography demonstrated more globular hearts and signs of cardiac dysfunction in IUGR. Second harmonic generation microscopy (SHGM) showed shorter sarcomere length and shorter A-band and thick-thin filament interaction lengths, that were already present in utero and persisted at 70 postnatal days (adulthood). Sarcomeric M-band (GO: 0031430) functional term was over-represented in IUGR fetal hearts.

CONCLUSION: The results suggest that IUGR induces cardiac dysfunction and permanent changes on the sarcomere.

}, keywords = {Animals, biomarkers, Blood Pressure, Body Weight, Disease Models, Animal, Echocardiography, Female, Fetal Growth Retardation, Fetal Heart, Fetus, Gene Expression Profiling, Organ Size, Placenta, Pregnancy, Rabbits, Sarcomeres}, issn = {1932-6203}, doi = {10.1371/journal.pone.0113067}, author = {Torre, Iratxe and Gonz{\'a}lez-Tendero, Anna and Garc{\'\i}a-Ca{\~n}adilla, Patricia and Crispi, F{\'a}tima and Garcia-Garcia, Francisco and Bijnens, Bart and Iruretagoyena, Igor and Dopazo, Joaquin and Amat-Rold{\'a}n, Ivan and Gratac{\'o}s, Eduard} } @article {505, title = {Mammosphere formation in breast carcinoma cell lines depends upon expression of E-cadherin.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e77281}, abstract = {

Tumors are heterogeneous at the cellular level where the ability to maintain tumor growth resides in discrete cell populations. Floating sphere-forming assays are broadly used to test stem cell activity in tissues, tumors and cell lines. Spheroids are originated from a small population of cells with stem cell features able to grow in suspension culture and behaving as tumorigenic in mice. We tested the ability of eleven common breast cancer cell lines representing the major breast cancer subtypes to grow as mammospheres, measuring the ability to maintain cell viability upon serial non-adherent passage. Only MCF7, T47D, BT474, MDA-MB-436 and JIMT1 were successfully propagated as long-term mammosphere cultures, measured as the increase in the number of viable cells upon serial non-adherent passages. Other cell lines tested (SKBR3, MDA-MB-231, MDA-MB-468 and MDA-MB-435) formed cell clumps that can be disaggregated mechanically, but cell viability drops dramatically on their second passage. HCC1937 and HCC1569 cells formed typical mammospheres, although they could not be propagated as long-term mammosphere cultures. All the sphere forming lines but MDA-MB-436 express E-cadherin on their surface. Knock down of E-cadherin expression in MCF-7 cells abrogated its ability to grow as mammospheres, while re-expression of E-cadherin in SKBR3 cells allow them to form mammospheres. Therefore, the mammosphere assay is suitable to reveal stem like features in breast cancer cell lines that express E-cadherin.

}, keywords = {Breast Neoplasms, Cadherins, Cell Line, Tumor, Cell Proliferation, Cluster Analysis, Female, gene expression, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, MCF-7 Cells, Neoplastic Stem Cells, Spheroids, Cellular, Tumor Cells, Cultured}, issn = {1932-6203}, doi = {10.1371/journal.pone.0077281}, author = {Manuel Iglesias, Juan and Beloqui, Izaskun and Garcia-Garcia, Francisco and Leis, Olatz and Vazquez-Martin, Alejandro and Eguiara, Arrate and Cufi, Silvia and Pavon, Andres and Menendez, Javier A and Dopazo, Joaquin and Martin, Angel G} } @article {1022, title = {Mammosphere Formation in Breast Carcinoma Cell Lines Depends upon Expression of E-cadherin}, journal = {PLoS ONE}, volume = {8}, year = {2013}, month = {2013/10/04}, pages = {e77281 -}, publisher = {Public Library of Science}, abstract = {

Tumors are heterogeneous at the cellular level where the ability to maintain tumor growth resides in discrete cell populations. Floating sphere-forming assays are broadly used to test stem cell activity in tissues, tumors and cell lines. Spheroids are originated from a small population of cells with stem cell features able to grow in suspension culture and behaving as tumorigenic in mice. We tested the ability of eleven common breast cancer cell lines representing the major breast cancer subtypes to grow as mammospheres, measuring the ability to maintain cell viability upon serial non-adherent passage. Only MCF7, T47D, BT474, MDA-MB-436 and JIMT1 were successfully propagated as long-term mammosphere cultures, measured as the increase in the number of viable cells upon serial non-adherent passages. Other cell lines tested (SKBR3, MDA-MB-231, MDA-MB-468 and MDA-MB-435) formed cell clumps that can be disaggregated mechanically, but cell viability drops dramatically on their second passage. HCC1937 and HCC1569 cells formed typical mammospheres, although they could not be propagated as long-term mammosphere cultures. All the sphere forming lines but MDA-MB-436 express E-cadherin on their surface. Knock down of E-cadherin expression in MCF-7 cells abrogated its ability to grow as mammospheres, while re-expression of E-cadherin in SKBR3 cells allow them to form mammospheres. Therefore, the mammosphere assay is suitable to reveal stem like features in breast cancer cell lines that express E-cadherin.

}, url = {http://dx.doi.org/10.1371\%2Fjournal.pone.0077281}, author = {Manuel Iglesias, Juan and Beloqui, Izaskun and Garcia-Garcia, Francisco and Leis, Olatz and Vazquez-Martin, Alejandro and Eguiara, Arrate and Cufi, Silvia and Pavon, Andres and Menendez, Javier A. and Dopazo, Joaquin and Martin, Angel G.} } @article {21266330, title = {Differential Lipid Partitioning Between Adipocytes and Tissue Macrophages Modulates Macrophage Lipotoxicity and M2/M1 Polarization in Obese Mice.}, journal = {Diabetes}, volume = {60}, number = {3}, year = {2011}, month = {2011 Jan 24}, pages = {797-809}, abstract = {

OBJECTIVE Obesity-associated insulin resistance is characterized by a state of chronic, low-grade inflammation that is associated with the accumulation of M1 proinflammatory macrophages in adipose tissue. Although different evidence explains the mechanisms linking the expansion of adipose tissue and adipose tissue macrophage (ATM) polarization, in the current study we investigated the concept of lipid-induced toxicity as the pathogenic link that could explain the trigger of this response. RESEARCH DESIGN AND METHODS We addressed this question using isolated ATMs and adipocytes from genetic and diet-induced murine models of obesity. Through transcriptomic and lipidomic analysis, we created a model integrating transcript and lipid species networks simultaneously occurring in adipocytes and ATMs and their reversibility by thiazolidinedione treatment. RESULTS We show that polarization of ATMs is associated with lipid accumulation and the consequent formation of foam cell-like cells in adipose tissue. Our study reveals that early stages of adipose tissue expansion are characterized by M2-polarized ATMs and that progressive lipid accumulation within ATMs heralds the M1 polarization, a macrophage phenotype associated with severe obesity and insulin resistance. Furthermore, rosiglitazone treatment, which promotes redistribution of lipids toward adipocytes and extends the M2 ATM polarization state, prevents the lipid alterations associated with M1 ATM polarization. CONCLUSIONS Our data indicate that the M1 ATM polarization in obesity might be a macrophage-specific manifestation of a more general lipotoxic pathogenic mechanism. This indicates that strategies to optimize fat deposition and repartitioning toward adipocytes might improve insulin sensitivity by preventing ATM lipotoxicity and M1 polarization.

}, author = {Prieur, Xavier and Mok, Crystal Y L and Velagapudi, Vidya R and N{\'u}{\~n}ez, Vanessa and Fuentes, Luc{\'\i}a and Montaner, David and Ishikawa, Ko and Camacho, Alberto and Barbarroja, Nuria and O{\textquoteright}Rahilly, Stephen and Sethi, Jaswinder and Dopazo, Joaquin and Oresic, Matej and Ricote, Mercedes and Vidal-Puig, Antonio} } @article {531, title = {Early peroxisome proliferator-activated receptor gamma regulated genes involved in expansion of pancreatic beta cell mass.}, journal = {BMC Med Genomics}, volume = {4}, year = {2011}, month = {2011 Dec 30}, pages = {86}, abstract = {

BACKGROUND: The progression towards type 2 diabetes depends on the allostatic response of pancreatic beta cells to synthesise and secrete enough insulin to compensate for insulin resistance. The endocrine pancreas is a plastic tissue able to expand or regress in response to the requirements imposed by physiological and pathophysiological states associated to insulin resistance such as pregnancy, obesity or ageing, but the mechanisms mediating beta cell mass expansion in these scenarios are not well defined. We have recently shown that ob/ob mice with genetic ablation of PPARγ2, a mouse model known as the POKO mouse failed to expand its beta cell mass. This phenotype contrasted with the appropriate expansion of the beta cell mass observed in their obese littermate ob/ob mice. Thus, comparison of these models islets particularly at early ages could provide some new insights on early PPARγ dependent transcriptional responses involved in the process of beta cell mass expansion

RESULTS: Here we have investigated PPARγ dependent transcriptional responses occurring during the early stages of beta cell adaptation to insulin resistance in wild type, ob/ob, PPARγ2 KO and POKO mice. We have identified genes known to regulate both the rate of proliferation and the survival signals of beta cells. Moreover we have also identified new pathways induced in ob/ob islets that remained unchanged in POKO islets, suggesting an important role for PPARγ in maintenance/activation of mechanisms essential for the continued function of the beta cell.

CONCLUSIONS: Our data suggest that the expansion of beta cell mass observed in ob/ob islets is associated with the activation of an immune response that fails to occur in POKO islets. We have also indentified other PPARγ dependent differentially regulated pathways including cholesterol biosynthesis, apoptosis through TGF-β signaling and decreased oxidative phosphorylation.

}, keywords = {Animals, Cell Proliferation, Cell Survival, Cholesterol, Down-Regulation, Female, Gene Expression Regulation, Gene Knockout Techniques, Insulin Resistance, Insulin-Secreting Cells, Mice, obesity, Oxidation-Reduction, Phosphorylation, PPAR gamma, Signal Transduction, Transcription, Genetic, Transforming Growth Factor beta}, issn = {1755-8794}, doi = {10.1186/1755-8794-4-86}, author = {Vivas, Yurena and Martinez-Garcia, Cristina and Izquierdo, Adriana and Garcia-Garcia, Francisco and Callejas, Sergio and Velasco, Ismael and Campbell, Mark and Ros, Manuel and Dopazo, Ana and Dopazo, Joaquin and Vidal-Puig, Antonio and Medina-Gomez, Gema} } @article {20676074, title = {The MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models.}, journal = {Nature biotechnology}, volume = {28}, year = {2010}, month = {2010 Aug}, pages = {827-38}, abstract = {

Gene expression data from microarrays are being applied to predict preclinical and clinical endpoints, but the reliability of these predictions has not been established. In the MAQC-II project, 36 independent teams analyzed six microarray data sets to generate predictive models for classifying a sample with respect to one of 13 endpoints indicative of lung or liver toxicity in rodents, or of breast cancer, multiple myeloma or neuroblastoma in humans. In total, \>30,000 models were built using many combinations of analytical methods. The teams generated predictive models without knowing the biological meaning of some of the endpoints and, to mimic clinical reality, tested the models on data that had not been used for training. We found that model performance depended largely on the endpoint and team proficiency and that different approaches generated models of similar performance. The conclusions and recommendations from MAQC-II should be useful for regulatory agencies, study committees and independent investigators that evaluate methods for global gene expression analysis.

}, url = {http://www.nature.com/nbt/journal/v28/n8/full/nbt.1665.html}, author = {Shi, Leming and Campbell, Gregory and Jones, Wendell D and Campagne, Fabien and Wen, Zhining and Walker, Stephen J and Su, Zhenqiang and Chu, Tzu-Ming and Goodsaid, Federico M and Pusztai, Lajos and Shaughnessy, John D and Oberthuer, Andr{\'e} and Thomas, Russell S and Paules, Richard S and Fielden, Mark and Barlogie, Bart and Chen, Weijie and Du, Pan and Fischer, Matthias and Furlanello, Cesare and Gallas, Brandon D and Ge, Xijin and Megherbi, Dalila B and Symmans, W Fraser and Wang, May D and Zhang, John and Bitter, Hans and Brors, Benedikt and Bushel, Pierre R and Bylesjo, Max and Chen, Minjun and Cheng, Jie and Cheng, Jing and Chou, Jeff and Davison, Timothy S and Delorenzi, Mauro and Deng, Youping and Devanarayan, Viswanath and Dix, David J and Dopazo, Joaquin and Dorff, Kevin C and Elloumi, Fathi and Fan, Jianqing and Fan, Shicai and Fan, Xiaohui and Fang, Hong and Gonzaludo, Nina and Hess, Kenneth R and Hong, Huixiao and Huan, Jun and Irizarry, Rafael A and Judson, Richard and Juraeva, Dilafruz and Lababidi, Samir and Lambert, Christophe G and Li, Li and Li, Yanen and Li, Zhen and Lin, Simon M and Liu, Guozhen and Lobenhofer, Edward K and Luo, Jun and Luo, Wen and McCall, Matthew N and Nikolsky, Yuri and Pennello, Gene A and Perkins, Roger G and Philip, Reena and Popovici, Vlad and Price, Nathan D and Qian, Feng and Scherer, Andreas and Shi, Tieliu and Shi, Weiwei and Sung, Jaeyun and Thierry-Mieg, Danielle and Thierry-Mieg, Jean and Thodima, Venkata and Trygg, Johan and Vishnuvajjala, Lakshmi and Wang, Sue Jane and Wu, Jianping and Wu, Yichao and Xie, Qian and Yousef, Waleed A and Zhang, Liang and Zhang, Xuegong and Zhong, Sheng and Zhou, Yiming and Zhu, Sheng and Arasappan, Dhivya and Bao, Wenjun and Lucas, Anne Bergstrom and Berthold, Frank and Brennan, Richard J and Buness, Andreas and Catalano, Jennifer G and Chang, Chang and Chen, Rong and Cheng, Yiyu and Cui, Jian and Czika, Wendy and Demichelis, Francesca and Deng, Xutao and Dosymbekov, Damir and Eils, Roland and Feng, Yang and Fostel, Jennifer and Fulmer-Smentek, Stephanie and Fuscoe, James C and Gatto, Laurent and Ge, Weigong and Goldstein, Darlene R and Guo, Li and Halbert, Donald N and Han, Jing and Harris, Stephen C and Hatzis, Christos and Herman, Damir and Huang, Jianping and Jensen, Roderick V and Jiang, Rui and Johnson, Charles D and Jurman, Giuseppe and Kahlert, Yvonne and Khuder, Sadik A and Kohl, Matthias and Li, Jianying and Li, Li and Li, Menglong and Li, Quan-Zhen and Li, Shao and Li, Zhiguang and Liu, Jie and Liu, Ying and Liu, Zhichao and Meng, Lu and Madera, Manuel and Martinez-Murillo, Francisco and Medina, Ignacio and Meehan, Joseph and Miclaus, Kelci and Moffitt, Richard A and Montaner, David and Mukherjee, Piali and Mulligan, George J and Neville, Padraic and Nikolskaya, Tatiana and Ning, Baitang and Page, Grier P and Parker, Joel and Parry, R Mitchell and Peng, Xuejun and Peterson, Ron L and Phan, John H and Quanz, Brian and Ren, Yi and Riccadonna, Samantha and Roter, Alan H and Samuelson, Frank W and Schumacher, Martin M and Shambaugh, Joseph D and Shi, Qiang and Shippy, Richard and Si, Shengzhu and Smalter, Aaron and Sotiriou, Christos and Soukup, Mat and Staedtler, Frank and Steiner, Guido and Stokes, Todd H and Sun, Qinglan and Tan, Pei-Yi and Tang, Rong and Tezak, Zivana and Thorn, Brett and Tsyganova, Marina and Turpaz, Yaron and Vega, Silvia C and Visintainer, Roberto and von Frese, Juergen and Wang, Charles and Wang, Eric and Wang, Junwei and Wang, Wei and Westermann, Frank and Willey, James C and Woods, Matthew and Wu, Shujian and Xiao, Nianqing and Xu, Joshua and Xu, Lei and Yang, Lun and Zeng, Xiao and Zhang, Jialu and Zhang, Li and Zhang, Min and Zhao, Chen and Puri, Raj K and Scherf, Uwe and Tong, Weida and Wolfinger, Russell D} } @article {19190944, title = {Membrane transporters and carbon metabolism implicated in chloride homeostasis differentiate salt stress responses in tolerant and sensitive Citrus rootstocks}, journal = {Funct Integr Genomics}, year = {2009}, note = {

Journal article Functional \& integrative genomics Funct Integr Genomics. 2009 Feb 4.

}, abstract = {

Salinity tolerance in Citrus is strongly related to leaf chloride accumulation. Both chloride homeostasis and specific genetic responses to Cl(-) toxicity are issues scarcely investigated in plants. To discriminate the transcriptomic network related to Cl(-) toxicity and salinity tolerance, we have used two Cl(-) salt treatments (NaCl and KCl) to perform a comparative microarray approach on two Citrus genotypes, the salt-sensitive Carrizo citrange, a poor Cl(-) excluder, and the tolerant Cleopatra mandarin, an efficient Cl(-) excluder. The data indicated that Cl(-) toxicity, rather than Na(+) toxicity and/or the concomitant osmotic perturbation, is the primary factor involved in the molecular responses of citrus plant leaves to salinity. A number of uncharacterized membrane transporter genes, like NRT1-2, were differentially regulated in the tolerant and the sensitive genotypes, suggesting its potential implication in Cl(-) homeostasis. Analyses of enriched functional categories showed that the tolerant rootstock induced wider stress responses in gene expression while repressing central metabolic processes such as photosynthesis and carbon utilization. These features were in agreement with phenotypic changes in the patterns of photosynthesis, transpiration, and stomatal conductance and support the concept that regulation of transpiration and its associated metabolic adjustments configure an adaptive response to salinity that reduces Cl(-) accumulation in the tolerant genotype.

}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=19190944}, author = {Brumos, J. and Colmenero-Flores, J. M. and A. Conesa and Izquierdo, P. and Sanchez, G. and Iglesias, D. J. and Lopez-Climent, M. F. and Gomez-Cadenas, A. and Talon, M.} } @article { PubMed_19781058, title = {Parallel changes in gene expression in peripheral blood mononuclear cells and the brain after maternal separation in the mouse.}, journal = {BMC Res Notes}, volume = {2}, year = {2009}, pages = {195}, issn = {1756-0500}, author = {Johan H van Heerden and Ana Conesa and Dan J Stein and Montaner, David and Vivienne Russell and Nicola Illing} } @article {17254327, title = {Analysis of 13000 unique Citrus clusters associated with fruit quality, production and salinity tolerance}, journal = {BMC Genomics}, volume = {8}, year = {2007}, note = {Terol, Javier Conesa, Ana Colmenero, Jose M Cercos, Manuel Tadeo, Francisco Agusti, Javier Alos, Enriqueta Andres, Fernando Soler, Guillermo Brumos, Javier Iglesias, Domingo J Gotz, Stefan Legaz, Francisco Argout, Xavier Courtois, Brigitte Ollitrault, Patrick Dossat, Carole Wincker, Patrick Morillon, Raphael Talon, Manuel Comparative Study Research Support, Non-U.S. Gov{\textquoteright}t England BMC genomics BMC Genomics. 2007 Jan 25;8:31.}, pages = {31}, abstract = {BACKGROUND: Improvement of Citrus, the most economically important fruit crop in the world, is extremely slow and inherently costly because of the long-term nature of tree breeding and an unusual combination of reproductive characteristics. Aside from disease resistance, major commercial traits in Citrus are improved fruit quality, higher yield and tolerance to environmental stresses, especially salinity. RESULTS: A normalized full length and 9 standard cDNA libraries were generated, representing particular treatments and tissues from selected varieties (Citrus clementina and C. sinensis) and rootstocks (C. reshni, and C. sinenis x Poncirus trifoliata) differing in fruit quality, resistance to abscission, and tolerance to salinity. The goal of this work was to provide a large expressed sequence tag (EST) collection enriched with transcripts related to these well appreciated agronomical traits. Towards this end, more than 54000 ESTs derived from these libraries were analyzed and annotated. Assembly of 52626 useful sequences generated 15664 putative transcription units distributed in 7120 contigs, and 8544 singletons. BLAST annotation produced significant hits for more than 80\% of the hypothetical transcription units and suggested that 647 of these might be Citrus specific unigenes. The unigene set, composed of 13000 putative different transcripts, including more than 5000 novel Citrus genes, was assigned with putative functions based on similarity, GO annotations and protein domains CONCLUSION: Comparative genomics with Arabidopsis revealed the presence of putative conserved orthologs and single copy genes in Citrus and also the occurrence of both gene duplication events and increased number of genes for specific pathways. In addition, phylogenetic analysis performed on the ammonium transporter family and glycosyl transferase family 20 suggested the existence of Citrus paralogs. Analysis of the Citrus gene space showed that the most important metabolic pathways known to affect fruit quality were represented in the unigene set. Overall, the similarity analyses indicated that the sequences of the genes belonging to these varieties and rootstocks were essentially identical, suggesting that the differential behaviour of these species cannot be attributed to major sequence divergences. This Citrus EST assembly contributes both crucial information to discover genes of agronomical interest and tools for genetic and genomic analyses, such as the development of new markers and microarrays.}, keywords = {Acclimatization/*genetics Amino Acid Motifs Citrus/*genetics Cluster Analysis Expressed Sequence Tags Fruit/genetics Gene Duplication *Gene Expression Regulation, Plant Gene Library Genes, Plant Genomics Molecular Sequence Data Multigene Family Phylogeny *Salts/adverse effects}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17254327}, author = {Terol, J. and A. Conesa and Colmenero, J. M. and Cercos, M. and Tadeo, F. and Agusti, J. and Alos, E. and Andres, F. and Soler, G. and Brumos, J. and Iglesias, D. J. and Gotz, S. and Legaz, F. and Argout, X. and Courtois, B. and Ollitrault, P. and Dossat, C. and Wincker, P. and Morillon, R. and Talon, M.} } @article {12499313, title = {ModView, visualization of multiple protein sequences and structures}, journal = {Bioinformatics}, volume = {19}, number = {1}, year = {2003}, note = {Ilyin, Valentin A Pieper, Ursula Stuart, Ashley C Marti-Renom, Marc A McMahan, Linda Sali, Andrej P50-GM62529/GM/NIGMS NIH HHS/United States Research Support, Non-U.S. Gov{\textquoteright}t Research Support, U.S. Gov{\textquoteright}t, P.H.S. England Bioinformatics (Oxford, England) Bioinformatics. 2003 Jan;19(1):165-6.}, pages = {165-6}, abstract = {SUMMARY: We describe ModView, a web application for visualization of multiple protein sequences and structures. ModView integrates a multiple structure viewer, a multiple sequence alignment editor, and a database querying engine. It is possible to interactively manipulate hundreds of proteins, to visualize conservative and variable residues, active and binding sites, fragments, and domains in protein families, as well as to display large macromolecular complexes such as ribosomes or viruses. As a Netscape plug-in, ModView can be included in HTML pages along with text and figures, which makes it useful for teaching and presentations. ModView is also suitable as a graphical interface to various databases because it can be controlled through JavaScript commands and called from CGI scripts. AVAILABILITY: ModView is available at http://guitar.rockefeller.edu/modview.}, keywords = {*Database Management Systems Documentation/methods Imaging, Protein/*methods *User-Computer Interface, Three-Dimensional/methods Protein Conformation Proteins/*chemistry/genetics Sequence Alignment/*methods Sequence Analysis}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=12499313}, author = {Ilyin, V. A. and Pieper, U. and Stuart, A. C. and M. A. Marti-Renom and McMahan, L. and Sali, A.} } @article {12824331, title = {Tools for comparative protein structure modeling and analysis}, journal = {Nucleic Acids Res}, volume = {31}, number = {13}, year = {2003}, note = {Eswar, Narayanan John, Bino Mirkovic, Nebojsa Fiser, Andras Ilyin, Valentin A Pieper, Ursula Stuart, Ashley C Marti-Renom, Marc A Madhusudhan, M S Yerkovich, Bozidar Sali, Andrej P50 GM62529/GM/NIGMS NIH HHS/United States R01 GM 54762/GM/NIGMS NIH HHS/United States R33 CA84699/CA/NCI NIH HHS/United States Research Support, Non-U.S. Gov{\textquoteright}t Research Support, U.S. Gov{\textquoteright}t, P.H.S. England Nucleic acids research Nucleic Acids Res. 2003 Jul 1;31(13):3375-80.}, pages = {3375-80}, abstract = {The following resources for comparative protein structure modeling and analysis are described (http://salilab.org): MODELLER, a program for comparative modeling by satisfaction of spatial restraints; MODWEB, a web server for automated comparative modeling that relies on PSI-BLAST, IMPALA and MODELLER; MODLOOP, a web server for automated loop modeling that relies on MODELLER; MOULDER, a CPU intensive protocol of MODWEB for building comparative models based on distant known structures; MODBASE, a comprehensive database of annotated comparative models for all sequences detectably related to a known structure; MODVIEW, a Netscape plugin for Linux that integrates viewing of multiple sequences and structures; and SNPWEB, a web server for structure-based prediction of the functional impact of a single amino acid substitution.}, keywords = {Amino Acid *Software *Structural Homology, Internet Models, Molecular Protein Folding Proteins/chemistry Reproducibility of Results Sequence Alignment Sequence Homology, Protein Systems Integration}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=12824331}, author = {Eswar, N. and John, B. and Mirkovic, N. and Fiser, A. and Ilyin, V. A. and Pieper, U. and Stuart, A. C. and M. A. Marti-Renom and Madhusudhan, M. S. and Yerkovich, B. and Sali, A.} } @article {12471146, title = {Use of single point mutations in domain I of beta 2-glycoprotein I to determine fine antigenic specificity of antiphospholipid autoantibodies}, journal = {J Immunol}, volume = {169}, number = {12}, year = {2002}, note = {Iverson, G Michael Reddel, Stephen Victoria, Edward J Cockerill, Keith A Wang, Ying-Xia Marti-Renom, Marc A Sali, Andrej Marquis, David M Krilis, Steven A Linnik, Matthew D GM54762/GM/NIGMS NIH HHS/United States Research Support, Non-U.S. Gov{\textquoteright}t Research Support, U.S. Gov{\textquoteright}t, P.H.S. United States Journal of immunology (Baltimore, Md. : 1950) J Immunol. 2002 Dec 15;169(12):7097-103.}, pages = {7097-103}, abstract = {Autoantibodies against beta(2)-glycoprotein I (beta(2)GPI) appear to be a critical feature of the antiphospholipid syndrome (APS). As determined using domain deletion mutants, human autoantibodies bind to the first of five domains present in beta(2)GPI. In this study the fine detail of the domain I epitope has been examined using 10 selected mutants of whole beta(2)GPI containing single point mutations in the first domain. The binding to beta(2)GPI was significantly affected by a number of single point mutations in domain I, particularly by mutations in the region of aa 40-43. Molecular modeling predicted these mutations to affect the surface shape and electrostatic charge of a facet of domain I. Mutation K19E also had an effect, albeit one less severe and involving fewer patients. Similar results were obtained in two different laboratories using affinity-purified anti-beta(2)GPI in a competitive inhibition ELISA and with whole serum in a direct binding ELISA. This study confirms that anti-beta(2)GPI autoantibodies bind to domain I, and that the charged surface patch defined by residues 40-43 contributes to a dominant target epitope.}, keywords = {Amino Acid Substitution/genetics Antibodies, Antibody/genetics Binding, Antiphospholipid/blood/*metabolism Antibodies, Competitive/genetics/immunology Enzyme-Linked Immunosorbent Assay/methods Epitopes/analysis/*immunology/metabolism Glycine/genetics Glycoproteins/biosynthesis/*genetics/*immunology/isolation \& purification/metabolism Humans Models, Molecular Peptide Fragments/genetics/immunology/isolation \& purification/metabolism *Point Mutation Protein Structure, Monoclonal/blood/metabolism Antiphospholipid Syndrome/immunology Arginine/genetics *Binding Sites, Tertiary/genetics Recombinant Proteins/biosynthesis/immunology/isolation \& purification/metabolism Static Electricity beta 2-Glycoprotein I}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=12471146}, author = {Iverson, G. M. and Reddel, S. and Victoria, E. J. and Cockerill, K. A. and Wang, Y. X. and M. A. Marti-Renom and Sali, A. and Marquis, D. M. and Krilis, S. A. and Linnik, M. D.} } @article {11524379, title = {DBAli: a database of protein structure alignments}, journal = {Bioinformatics}, volume = {17}, number = {8}, year = {2001}, note = {Marti-Renom, M A Ilyin, V A Sali, A Research Support, Non-U.S. Gov{\textquoteright}t Research Support, U.S. Gov{\textquoteright}t, P.H.S. England Bioinformatics (Oxford, England) Bioinformatics. 2001 Aug;17(8):746-7.}, pages = {746-7}, abstract = {SUMMARY: The DBAli database includes approximately 35000 alignments of pairs of protein structures from SCOP (Lo Conte et al., Nucleic Acids Res., 28, 257-259, 2000) and CE (Shindyalov and Bourne, Protein Eng., 11, 739-747, 1998). DBAli is linked to several resources, including Compare3D (Shindyalov and Bourne, http://www.sdsc.edu/pb/software.htm, 1999) and ModView (Ilyin and Sali, http://guitar.rockefeller.edu/ModView/, 2001) for visualizing sequence alignments and structure superpositions. A flexible search of DBAli by protein sequence and structure properties allows construction of subsets of alignments suitable for a number of applications, such as benchmarking of sequence-sequence and sequence-structure alignment methods under a variety of conditions. AVAILABILITY: http://guitar.rockefeller.edu/DBAli/}, keywords = {Computational Biology *Databases, Protein Proteins/*chemistry/*genetics Sequence Alignment/*statistics \& numerical data Software Software Design}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=11524379}, author = {M. A. Marti-Renom and Ilyin, V. A. and Sali, A.} }