Centro Pfizer-Andalucía de Genómica e Investigación Oncológica (GENYO)

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Recent Submissions

Now showing 1 - 20 of 366
  • Publication
    A 5-FU Precursor Designed to Evade Anabolic and Catabolic Drug Pathways and Activated by Pd Chemistry In Vitro and In Vivo.
    (2022-01-03) Adam, Catherine; Bray, Thomas L; Pérez-López, Ana M; Tan, Ee Hong; Rubio-Ruiz, Belén; Baillache, Daniel J; Houston, Douglas R; Salji, Mark J; Leung, Hing Y; Unciti-Broceta, Asier
    5-Fluorouracil (5-FU) is an antineoplastic antimetabolite that is widely administered to cancer patients by bolus injection, especially to those suffering from colorectal and pancreatic cancer. Because of its suboptimal route of administration and dose-limiting toxicities, diverse 5-FU prodrugs have been developed to confer oral bioavailability and increase the safety profile of 5-FU chemotherapy regimens. Our contribution to this goal is presented herein with the development of a novel palladium-activated prodrug designed to evade the metabolic machinery responsible for 5-FU anabolic activation and catabolic processing. The new prodrug is completely innocuous to cells and highly resistant to metabolization by primary hepatocytes and liver S9 fractions (the main metabolic route for 5-FU degradation), whereas it is rapidly converted into 5-FU in the presence of a palladium (Pd) source. In vivo pharmokinetic analysis shows the prodrug is rapidly and completely absorbed after oral administration and exhibits a longer half-life than 5-FU. In vivo efficacy studies in a xenograft colon cancer model served to prove, for the first time, that orally administered prodrugs can be locally converted to active drugs by intratumorally inserted Pd implants.
  • Publication
    Hybrid Fluorescent Mass-Tag Nanotrackers as Universal Reagents for Long-Term Live-Cell Barcoding.
    (2022-07-22) Delgado-Gonzalez, Antonio; Laz-Ruiz, Jose Antonio; Cano-Cortes, M Victoria; Huang, Ying-Wen; Gonzalez, Veronica D; Diaz-Mochon, Juan Jose; Fantl, Wendy J; Sanchez-Martin, Rosario M
    Barcoding and pooling cells for processing as a composite sample are critical to minimize technical variability in multiplex technologies. Fluorescent cell barcoding has been established as a standard method for multiplexing in flow cytometry analysis. In parallel, mass-tag barcoding is routinely used to label cells for mass cytometry. Barcode reagents currently used label intracellular proteins in fixed and permeabilized cells and, therefore, are not suitable for studies with live cells in long-term culture prior to analysis. In this study, we report the development of fluorescent palladium-based hybrid-tag nanotrackers to barcode live cells for flow and mass cytometry dual-modal readout. We describe the preparation, physicochemical characterization, efficiency of cell internalization, and durability of these nanotrackers in live cells cultured over time. In addition, we demonstrate their compatibility with standardized cytometry reagents and protocols. Finally, we validated these nanotrackers for drug response assays during a long-term coculture experiment with two barcoded cell lines. This method represents a new and widely applicable advance for fluorescent and mass-tag barcoding that is independent of protein expression levels and can be used to label cells before long-term drug studies.
  • Publication
    Protocol for large scale whole blood immune monitoring by mass cytometry and Cyto Quality Pipeline.
    (2022-10-31) Rybakowska, Paulina; Van Gassen, Sofie; Martorell Marugán, Jordi; Quintelier, Katrien; Saeys, Yvan; Alarcón-Riquelme, Marta E; Marañón, Concepción
    Mass cytometry (MC) is a powerful large-scale immune monitoring technology. To maximize MC data quality, we present a protocol for whole blood analysis together with an R package, Cyto Quality Pipeline (CytoQP), which minimizes the experimental artifacts and batch effects to ensure data reproducibility. We describe the steps to stimulate, fix, and freeze blood samples before acquisition to make them suitable for retrospective studies. We then detail the use of barcoding and reference samples to facilitate multicenter and multi-batch experiments. For complete details on the use and execution of this protocol, please refer to Rybakowska et al. (2021a) and (2021b).
  • Publication
    The Q-junction and the inflammatory response are critical pathological and therapeutic factors in CoQ deficiency.
    (2022-07-15) González-García, Pilar; Díaz-Casado, María Elena; Hidalgo-Gutiérrez, Agustín; Jiménez-Sánchez, Laura; Bakkali, Mohammed; Barriocanal-Casado, Eliana; Escames, Germaine; Chiozzi, Riccardo Zenezini; Völlmy, Franziska; Zaal, Esther A; Berkers, Celia R; Heck, Albert J R; López, Luis C
    Defects in Coenzyme Q (CoQ) metabolism have been associated with primary mitochondrial disorders, neurodegenerative diseases and metabolic conditions. The consequences of CoQ deficiency have not been fully addressed, and effective treatment remains challenging. Here, we use mice with primary CoQ deficiency (Coq9R239X), and we demonstrate that CoQ deficiency profoundly alters the Q-junction, leading to extensive changes in the mitochondrial proteome and metabolism in the kidneys and, to a lesser extent, in the brain. CoQ deficiency also induces reactive gliosis, which mediates a neuroinflammatory response, both of which lead to an encephalopathic phenotype. Importantly, treatment with either vanillic acid (VA) or β-resorcylic acid (β-RA), two analogs of the natural precursor for CoQ biosynthesis, partially restores CoQ metabolism, particularly in the kidneys, and induces profound normalization of the mitochondrial proteome and metabolism, ultimately leading to reductions in gliosis, neuroinflammation and spongiosis and, consequently, reversing the phenotype. Together, these results provide key mechanistic insights into defects in CoQ metabolism and identify potential disease biomarkers. Furthermore, our findings clearly indicate that the use of analogs of the CoQ biosynthetic precursor is a promising alternative therapy for primary CoQ deficiency and has potential for use in the treatment of more common neurodegenerative and metabolic diseases that are associated with secondary CoQ deficiency.
  • Publication
    Physiological lentiviral vectors for the generation of improved CAR-T cells.
    (2022-05-18) Tristán-Manzano, María; Maldonado-Pérez, Noelia; Justicia-Lirio, Pedro; Muñoz, Pilar; Cortijo-Gutiérrez, Marina; Pavlovic, Kristina; Jiménez-Moreno, Rosario; Nogueras, Sonia; Carmona, M Dolores; Sánchez-Hernández, Sabina; Aguilar-González, Araceli; Castella, María; Juan, Manel; Marañón, Concepción; Marchal, Juan Antonio; Benabdellah, Karim; Herrera, Concha; Martin, Francisco
    Anti-CD19 chimeric antigen receptor (CAR)-T cells have achieved impressive outcomes for the treatment of relapsed and refractory B-lineage neoplasms. However, important limitations still remain due to severe adverse events (i.e., cytokine release syndrome and neuroinflammation) and relapse of 40%-50% of the treated patients. Most CAR-T cells are generated using retroviral vectors with strong promoters that lead to high CAR expression levels, tonic signaling, premature exhaustion, and overstimulation, reducing efficacy and increasing side effects. Here, we show that lentiviral vectors (LVs) expressing the transgene through a WAS gene promoter (AW-LVs) closely mimic the T cell receptor (TCR)/CD3 expression kinetic upon stimulation. These AW-LVs can generate improved CAR-T cells as a consequence of their moderate and TCR-like expression profile. Compared with CAR-T cells generated with human elongation factor α (EF1α)-driven-LVs, AW-CAR-T cells exhibited lower tonic signaling, higher proportion of naive and stem cell memory T cells, less exhausted phenotype, and milder secretion of tumor necrosis factor alpha (TNF-α) and interferon (IFN)-ɣ after efficient destruction of CD19+ lymphoma cells, both in vitro and in vivo. Moreover, we also showed their improved efficiency using an in vitro CD19+ pancreatic tumor model. We finally demonstrated the feasibility of large-scale manufacturing of AW-CAR-T cells in guanosine monophosphate (GMP)-like conditions. Based on these data, we propose the use of AW-LVs for the generation of improved CAR-T products.
  • Publication
    Reversal of mitochondrial malate dehydrogenase 2 enables anaplerosis via redox rescue in respiration-deficient cells.
    (2022-11-02) Altea-Manzano, Patricia; Vandekeere, Anke; Edwards-Hicks, Joy; Roldan, Mar; Abraham, Emily; Lleshi, Xhordi; Guerrieri, Ania Naila; Berardi, Domenica; Wills, Jimi; Junior, Jair Marques; Pantazi, Asimina; Acosta, Juan Carlos; Sanchez-Martin, Rosario M; Fendt, Sarah-Maria; Martin-Hernandez, Miguel; Finch, Andrew J
    Inhibition of the electron transport chain (ETC) prevents the regeneration of mitochondrial NAD+, resulting in cessation of the oxidative tricarboxylic acid (TCA) cycle and a consequent dependence upon reductive carboxylation for aspartate synthesis. NAD+ regeneration alone in the cytosol can rescue the viability of ETC-deficient cells. Yet, how this occurs and whether transfer of oxidative equivalents to the mitochondrion is required remain unknown. Here, we show that inhibition of the ETC drives reversal of the mitochondrial aspartate transaminase (GOT2) as well as malate and succinate dehydrogenases (MDH2 and SDH) to transfer oxidative NAD+ equivalents into the mitochondrion. This supports the NAD+-dependent activity of the mitochondrial glutamate dehydrogenase (GDH) and thereby enables anaplerosis-the entry of glutamine-derived carbon into the TCA cycle and connected biosynthetic pathways. Thus, under impaired ETC function, the cytosolic redox state is communicated into the mitochondrion and acts as a rheostat to support GDH activity and cell viability.
  • Publication
    Pathogenic mechanisms involving the interplay between adipose tissue and auto-antibodies in rheumatoid arthritis.
    (2022-08-06) Arias-de la Rosa, Iván; Escudero-Contreras, Alejandro; Ruiz-Ponce, Miriam; Cuesta-López, Laura; Román-Rodríguez, Cristóbal; Pérez-Sánchez, Carlos; Ruiz-Limón, Patricia; Ruiz, Rocío Guzman-; Leiva-Cepas, Fernando; Alcaide, Juan; Segui, Pedro; Plasencia, Chamaida; Martinez-Feito, Ana; Font, Pilar; Ábalos, María C; Ortega, Rafaela; Malagón, María M; Tinahones, Francisco J; Collantes-Estévez, Eduardo; López-Pedrera, Chary; Barbarroja, Nuria
    We aimed to evaluate the association between adipose tissue (AT) dysfunction, autoimmunity, and disease activity in rheumatoid arthritis (RA). A cross-sectional study including 150 RA patients and 50 healthy donors and longitudinal study with 122 RA patients treated with anti-tumor necrosis factor (TNF)-α, anti-interleukin 6 receptor (IL6R) or anti-CD20 therapies for 6 months were carried out. In vitro experiments with human AT and adipocyte and macrophage cell lines were performed. A collagen-induced arthritis mouse model was developed. The insulin resistance and the altered adipocytokine profile were associated with disease activity, the presence of anti-citrullinated proteins anti-bodies (ACPAs), and worse response to therapy in RA. AT in the context of arthritis is characterized by an inflammatory state alongside the infiltration of macrophages and B/plasmatic cells, where ACPAs can have a direct impact, inducing inflammation and insulin resistance in macrophages and promoting a defective adipocyte differentiation, partially restored by biologicals.
  • Publication
    Parabacteroides goldsteinii abdominal infection in a patient with lymphoma.
    (2021-05-18) Cobo, Fernando; Pérez-Carrasco, Virginia; Gómez-Vicente, Esther; Martín-Hita, Lina; García-Salcedo, José A; Navarro-Marí, José María
  • Publication
    Characterisation of retrotransposon insertion polymorphisms in whole genome sequencing data from individuals with amyotrophic lateral sclerosis.
    (2022-08-10) Savage, Abigail L; Iacoangeli, Alfredo; Schumann, Gerald G; Rubio-Roldan, Alejandro; Garcia-Perez, Jose L; Al Khleifat, Ahmad; Koks, Sulev; Bubb, Vivien J; Al-Chalabi, Ammar; Quinn, John P
    The genetics of an individual is a crucial factor in understanding the risk of developing the neurodegenerative disease amyotrophic lateral sclerosis (ALS). There is still a large proportion of the heritability of ALS, particularly in sporadic cases, to be understood. Among others, active transposable elements drive inter-individual variability, and in humans long interspersed element 1 (LINE1, L1), Alu and SINE-VNTR-Alu (SVA) retrotransposons are a source of polymorphic insertions in the population. We undertook a pilot study to characterise the landscape of non-reference retrotransposon insertion polymorphisms (non-ref RIPs) in 15 control and 15 ALS individuals' whole genomes from Project MinE, an international project to identify potential genetic causes of ALS. The combination of two bioinformatics tools (mobile element locator tool (MELT) and TEBreak) identified on average 1250 Alu, 232 L1 and 77 SVA non-ref RIPs per genome across the 30 analysed. Further PCR validation of individual polymorphic retrotransposon insertions showed a similar level of accuracy for MELT and TEBreak. Our preliminary study did not identify a specific RIP or a significant difference in the total number of non-ref RIPs in ALS compared to control genomes. The use of multiple bioinformatic tools improved the accuracy of non-ref RIP detection and our study highlights the potential importance of studying these elements further in ALS.
  • Publication
    An oleuropein rich-olive (Olea europaea L.) leaf extract reduces β-amyloid and tau proteotoxicity through regulation of oxidative- and heat shock-stress responses in Caenorhabditis elegans.
    (2022-03-08) Romero-Márquez, Jose M; Navarro-Hortal, María D; Jiménez-Trigo, Victoria; Vera-Ramírez, Laura; Forbes-Hernández, Tamara J; Esteban-Muñoz, Adelaida; Giampieri, Francesca; Bullón, Pedro; Battino, Maurizio; Sánchez-González, Cristina; Quiles, José L
    Olive tree-derived products have been associated with numerous benefits for health. The aim of the present study was to characterize an olive leaf extract enriched in oleuropein (OLE) concerning phenolic content and profile as well as antioxidant capacity. Short-term and long-term toxicity, including oxidative stress, was in vivo evaluated in the experimental model Caenorhabditis elegans. Moreover, the potential therapeutic effect of the extract against Aβ induced- and tau protein induced-toxicity was also evaluated in C. elegans. OLE treatment did not exert toxicity. On the contrary, the extract was able to ameliorate oxidative stress and proteotoxicity related to Aβ and tau aggregation. The potential molecular mechanisms present behind the observed results explored by RNAi technology revealed that DAF-16/FOXO and SKN-1/NRF2, elements of the insulin insulin-like signalling pathway, as well as HSP-16.2 overexpression were involved.
  • Publication
    SIDT1 plays a key role in type I IFN responses to nucleic acids in plasmacytoid dendritic cells and mediates the pathogenesis of an imiquimod-induced psoriasis model.
    (2022-01-19) Morell, María; Varela, Nieves; Castillejo-López, Casimiro; Coppard, Céline; Luque, María José; Wu, Ying-Yu; Martín-Morales, Natividad; Pérez-Cózar, Francisco; Gómez-Hernández, Gonzalo; Kumar, Ramesh; O'Valle, Francisco; Alarcón-Riquelme, Marta E; Marañón, Concepción
    Type I IFN (IFN-I) is a family of cytokines involved in the pathogenesis of autoimmune and autoinflammatory diseases such as psoriasis. SIDT1 is an ER-resident protein expressed in the lymphoid lineage, and involved in anti-viral IFN-I responses in vivo, through an unclear mechanism. Herein we have dissected the role of SIDT1 in the natural IFN-producing cells, the plasmacytoid dendritic cells (pDC). The function of SIDT1 in pDC was determined by silencing its expression in human primary pDC and GEN2.2 cell line. SIDT1 role in vivo was assessed using the imiquimod-induced psoriasis model in the SIDT1-deficient mice (sidt1-/-). Silencing of SIDT1 in GEN2.2 led to a blockade of the IFN-I response after stimulation of TLR7 and TLR9, without affecting the pro-inflammatory responses or upregulation of maturation markers. We found that SIDT1 migrates from the ER to the endosomal and lysosomal compartments together with TLR9 after CpG stimulation, participating in the access of the TLR9-CpG complex to lysosome-related vesicles, and therefore mediating the activation of TBK1 and the nuclear migration of IRF7, but not of NF-κB. sidt1-/- mice showed a significant decrease in severity parameters of the imiquimod-induced acute psoriasis-like model, associated with a decrease in the production of IFN-I and IFN-dependent chemokines. Our findings indicate that SIDT1 is at the cross-road between the IFN-I and the proinflammatory pathways and constitutes a promising drug target for psoriasis and other diseases mediated by IFN-I responses. This work was supported by the Consejería de Salud y Familias de la Junta de Andalucía (PIER_S1149 and C2_S0050) and Instituto de Salud Carlos III (PI18/00082 and PI21/01151), partly supported by European FEDER funds, and prior funding to MEAR from the Alliance for Lupus Research and the Swedish Research Council.
  • Publication
    The mitochondrial pyruvate carrier regulates memory T cell differentiation and antitumor function.
    (2022-04-21) Wenes, Mathias; Jaccard, Alison; Wyss, Tania; Maldonado-Pérez, Noelia; Teoh, Shao Thing; Lepez, Anouk; Renaud, Fabrice; Franco, Fabien; Waridel, Patrice; Yacoub Maroun, Céline; Tschumi, Benjamin; Dumauthioz, Nina; Zhang, Lianjun; Donda, Alena; Martín, Francisco; Migliorini, Denis; Lunt, Sophia Y; Ho, Ping-Chih; Romero, Pedro
    Glycolysis, including both lactate fermentation and pyruvate oxidation, orchestrates CD8+ T cell differentiation. However, how mitochondrial pyruvate metabolism and uptake controlled by the mitochondrial pyruvate carrier (MPC) impact T cell function and fate remains elusive. We found that genetic deletion of MPC drives CD8+ T cell differentiation toward a memory phenotype. Metabolic flexibility induced by MPC inhibition facilitated acetyl-coenzyme-A production by glutamine and fatty acid oxidation that results in enhanced histone acetylation and chromatin accessibility on pro-memory genes. However, in the tumor microenvironment, MPC is essential for sustaining lactate oxidation to support CD8+ T cell antitumor function. We further revealed that chimeric antigen receptor (CAR) T cell manufacturing with an MPC inhibitor imprinted a memory phenotype and demonstrated that infusing MPC inhibitor-conditioned CAR T cells resulted in superior and long-lasting antitumor activity. Altogether, we uncover that mitochondrial pyruvate uptake instructs metabolic flexibility for guiding T cell differentiation and antitumor responses.
  • Publication
    A pleiotropic variant in DNAJB4 is associated with multiple myeloma risk.
    (2022-10-01) Dicanio, Marco; Giaccherini, Matteo; Clay-Gilmour, Alyssa; Macauda, Angelica; Sainz, Juan; Machiela, Mitchell J; Rybicka-Ramos, Malwina; Norman, Aaron D; Tyczyńska, Agata; Chanock, Stephen J; Barington, Torben; Kumar, Shaji K; Bhatti, Parveen; Cozen, Wendy; Brown, Elizabeth E; Suska, Anna; Haastrup, Eva K; Orlowski, Robert Z; Dudziński, Marek; Garcia-Sanz, Ramon; Kruszewski, Marcin; Martinez-Lopez, Joaquin; Beider, Katia; Iskierka-Jazdzewska, Elżbieta; Pelosini, Matteo; Berndt, Sonja I; Raźny, Małgorzata; Jamroziak, Krzysztof; Rajkumar, S Vincent; Jurczyszyn, Artur; Vangsted, Annette Juul; Collado, Pilar Garrido; Vogel, Ulla; Hofmann, Jonathan N; Petrini, Mario; Butrym, Aleksandra; Slager, Susan L; Ziv, Elad; Subocz, Edyta; Giles, Graham G; Andersen, Niels Frost; Mazur, Grzegorz; Watek, Marzena; Lesueur, Fabienne; Hildebrandt, Michelle A T; Zawirska, Daria; Ebbesen, Lene Hyldahl; Marques, Herlander; Gemignani, Federica; Dumontet, Charles; Várkonyi, Judit; Buda, Gabriele; Nagler, Arnon; Druzd-Sitek, Agnieszka; Wu, Xifeng; Kadar, Katalin; Camp, Nicola J; Grzasko, Norbert; Waller, Rosalie G; Vachon, Celine; Canzian, Federico; Campa, Daniele
    Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P 
  • Publication
    Pharmacogenetics of siponimod: A systematic review.
    (2022-08-12) Díaz-Villamarín, Xando; Piñar-Morales, Raquel; Barrero-Hernández, Francisco Javier; Antúnez-Rodríguez, Alba; Cabeza-Barrera, José; Morón-Romero, Rocío
    Multiple sclerosis is a chronic inflammatory neurological disease, and siponimod (Mayzent) is the first oral treatment option for adult patients with secondary progressive multiple sclerosis. We performed a systematic review of the pharmacogenetics of Siponimod, and we found that (430 C>T; rs1799853) and CYP2C9 * 3 (1075 A>C; rs1057910), both translated no-function alleles, have been related to a lower metabolism of siponimod by CYP2C9 enzyme. The FDA-approved drug label and EMA risk management plan for siponimod require testing patients for CYP2C9 genotype before treatment starts. The FDA drug label states that siponimod is contraindicated in patients carrying a CYP2C9 * 3/* 3 genotype, and a daily maintenance dose of 1 mg in patients with CYP2C9 * 1/* 3 and * 2/* 3 genotypes. The EMA reported the potential long-term safety implications in CYP2C9 poor metabolizer patients treated with this drug. Based on this systematic review we concluded that CYP2C9 SNPs influence on siponimod response might be stated by assessing not only CYP2C9 * 2 and CYP2C9 * 3 but other genetic variants resulting in CYP2C9 IM/PM status. CYP2C9 IM phenotype translated from the CYP2C9 * 2 genotype should be revised since it is contradictory compared to other CYP2C9 no-function alleles, and CYP2C9 * 2 might be excluded from PGx testing recommendation before treatment starts with siponimod since it is not translated into a therapeutic recommendation.
  • Publication
    Cells electric charge analyses define specific properties for cancer cells activity.
    (2021-12-01) Moleón Baca, J A; Ontiveros Ortega, A; Aránega Jiménez, A; Granados Principal, S
    The surface electrical charge of cells is conditioned by the ionic medium in which they are immersed. This charge is specific for each cell type and is especially important in tumour cells because it determines their state of aggregation and their adhesion in the different organs. This study analyses the variations in surface charge of cells when pH, electrolytes, and their concentration are modified. The modification of these factors leads to changes in the surface charge of tumour cells; therefore, their states of aggregation and behaviour can be modified. This may even have a use in the prognosis and treatment of various tumours. Some studies conclude that the activity associated with the glycolysis process is accompanied by a change in the surface charge of cells. Notably, there is a high rate of glycolysis in tumours. Our results show that surface charge of cells strongly depends on nature of ionic medium in which they are found, with the valence of the majority ion being the most important factor. When ionic strength was high, the charge decreased dramatically. On the other hand, charge becomes zero or positive in an acidic pH, while in a basic pH, the negative charge increases.
  • Publication
    Defective α-tectorin may involve tectorial membrane in familial Meniere disease.
    (2022) Roman-Naranjo, Pablo; Parra-Perez, Alberto M; Escalera-Balsera, Alba; Soto-Varela, Andres; Gallego-Martinez, Alvaro; Aran, Ismael; Perez-Fernandez, Nicolas; Bächinger, David; Eckhard, Andreas H; Gonzalez-Aguado, Rocio; Frejo, Lidia; Lopez-Escamez, Jose A
  • Publication
    A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids.
    (2022) Ramdas, Shweta; Judd, Jonathan; Graham, Sarah E; Kanoni, Stavroula; Wang, Yuxuan; Surakka, Ida; Wenz, Brandon; Clarke, Shoa L; Chesi, Alessandra; Wells, Andrew; Bhatti, Konain Fatima; Vedantam, Sailaja; Winkler, Thomas W; Locke, Adam E; Marouli, Eirini; Zajac, Greg J M; Wu, Kuan-Han H; Ntalla, Ioanna; Hui, Qin; Klarin, Derek; Hilliard, Austin T; Wang, Zeyuan; Xue, Chao; Thorleifsson, Gudmar; Helgadottir, Anna; Gudbjartsson, Daniel F; Holm, Hilma; Olafsson, Isleifur; Hwang, Mi Yeong; Han, Sohee; Akiyama, Masato; Sakaue, Saori; Terao, Chikashi; Kanai, Masahiro; Zhou, Wei; Brumpton, Ben M; Rasheed, Humaira; Havulinna, Aki S; Veturi, Yogasudha; Pacheco, Jennifer Allen; Rosenthal, Elisabeth A; Lingren, Todd; Feng, QiPing; Kullo, Iftikhar J; Narita, Akira; Takayama, Jun; Martin, Hilary C; Hunt, Karen A; Trivedi, Bhavi; Haessler, Jeffrey; Giulianini, Franco; Bradford, Yuki; Miller, Jason E; Campbell, Archie; Lin, Kuang; Millwood, Iona Y; Rasheed, Asif; Hindy, George; Faul, Jessica D; Zhao, Wei; Weir, David R; Turman, Constance; Huang, Hongyan; Graff, Mariaelisa; Choudhury, Ananyo; Sengupta, Dhriti; Mahajan, Anubha; Brown, Michael R; Zhang, Weihua; Yu, Ketian; Schmidt, Ellen M; Pandit, Anita; Gustafsson, Stefan; Yin, Xianyong; Luan, Jian'an; Zhao, Jing-Hua; Matsuda, Fumihiko; Jang, Hye-Mi; Yoon, Kyungheon; Medina-Gomez, Carolina; Pitsillides, Achilleas; Hottenga, Jouke Jan; Wood, Andrew R; Ji, Yingji; Gao, Zishan; Haworth, Simon; Mitchell, Ruth E; Chai, Jin Fang; Aadahl, Mette; Bjerregaard, Anne A; Yao, Jie; Manichaikul, Ani; Lee, Wen-Jane; Hsiung, Chao Agnes; Warren, Helen R; Ramirez, Julia; Bork-Jensen, Jette; Kårhus, Line L; Goel, Anuj; Sabater-Lleal, Maria; Noordam, Raymond; Mauro, Pala; Matteo, Floris; McDaid, Aaron F; Marques-Vidal, Pedro; Wielscher, Matthias; Trompet, Stella; Sattar, Naveed; Møllehave, Line T; Munz, Matthias; Zeng, Lingyao; Huang, Jianfeng; Yang, Bin; Poveda, Alaitz; Kurbasic, Azra; Schönherr, Sebastian; Forer, Lukas; Scholz, Markus; Galesloot, Tessel E; Bradfield, Jonathan P; Ruotsalainen, Sanni E; Daw, E Warwick; Zmuda, Joseph M; Mitchell, Jonathan S; Fuchsberger, Christian; Christensen, Henry; Brody, Jennifer A; Le, Phuong; Feitosa, Mary F; Wojczynski, Mary K; Hemerich, Daiane; Preuss, Michael; Mangino, Massimo; Christofidou, Paraskevi; Verweij, Niek; Benjamins, Jan W; Engmann, Jorgen; Noah, Tsao L; Verma, Anurag; Slieker, Roderick C; Lo, Ken Sin; Zilhao, Nuno R; Kleber, Marcus E; Delgado, Graciela E; Huo, Shaofeng; Ikeda, Daisuke D; Iha, Hiroyuki; Yang, Jian; Liu, Jun; Demirkan, Ayşe; Leonard, Hampton L; Marten, Jonathan; Emmel, Carina; Schmidt, Börge; Smyth, Laura J; Cañadas-Garre, Marisa; Wang, Chaolong; Nakatochi, Masahiro; Wong, Andrew; Hutri-Kähönen, Nina; Sim, Xueling; Xia, Rui; Huerta-Chagoya, Alicia; Fernandez-Lopez, Juan Carlos; Lyssenko, Valeriya; Nongmaithem, Suraj S; Sankareswaran, Alagu; Irvin, Marguerite R; Oldmeadow, Christopher; Kim, Han-Na; Ryu, Seungho; Timmers, Paul R H J; Arbeeva, Liubov; Dorajoo, Rajkumar; Lange, Leslie A; Prasad, Gauri; Lorés-Motta, Laura; Pauper, Marc; Long, Jirong; Li, Xiaohui; Theusch, Elizabeth; Takeuchi, Fumihiko; Spracklen, Cassandra N; Loukola, Anu; Bollepalli, Sailalitha; Warner, Sophie C; Wang, Ya Xing; Wei, Wen B; Nutile, Teresa; Ruggiero, Daniela; Sung, Yun Ju; Chen, Shufeng; Liu, Fangchao; Yang, Jingyun; Kentistou, Katherine A; Banas, Bernhard; Morgan, Anna; Meidtner, Karina; Bielak, Lawrence F; Smith, Jennifer A; Hebbar, Prashantha; Farmaki, Aliki-Eleni; Hofer, Edith; Lin, Maoxuan; Concas, Maria Pina; Vaccargiu, Simona; van der Most, Peter J; Pitkänen, Niina; Cade, Brian E; van der Laan, Sander W; Chitrala, Kumaraswamy Naidu; Weiss, Stefan; Bentley, Amy R; Doumatey, Ayo P; Adeyemo, Adebowale A; Lee, Jong Young; Petersen, Eva R B; Nielsen, Aneta A; Choi, Hyeok Sun; Nethander, Maria; Freitag-Wolf, Sandra; Southam, Lorraine; Rayner, Nigel W; Wang, Carol A; Lin, Shih-Yi; Wang, Jun-Sing; Couture, Christian; Lyytikäinen, Leo-Pekka; Nikus, Kjell; Cuellar-Partida, Gabriel; Vestergaard, Henrik; Hidalgo, Bertha; Giannakopoulou, Olga; Cai, Qiuyin; Obura, Morgan O; van Setten, Jessica; He, Karen Y; Tang, Hua; Terzikhan, Natalie; Shin, Jae Hun; Jackson, Rebecca D; Reiner, Alexander P; Martin, Lisa Warsinger; Chen, Zhengming; Li, Liming; Kawaguchi, Takahisa; Thiery, Joachim; Bis, Joshua C; Launer, Lenore J; Li, Huaixing; Nalls, Mike A; Raitakari, Olli T; Ichihara, Sahoko; Wild, Sarah H; Nelson, Christopher P; Campbell, Harry; Jäger, Susanne; Nabika, Toru; Al-Mulla, Fahd; Niinikoski, Harri; Braund, Peter S; Kolcic, Ivana; Kovacs, Peter; Giardoglou, Tota; Katsuya, Tomohiro; de Kleijn, Dominique; de Borst, Gert J; Kim, Eung Kweon; Adams, Hieab H H; Ikram, M Arfan; Zhu, Xiaofeng; Asselbergs, Folkert W; Kraaijeveld, Adriaan O; Beulens, Joline W J; Shu, Xiao-Ou; Rallidis, Loukianos S; Pedersen, Oluf; Hansen, Torben; Mitchell, Paul; Hewitt, Alex W; Kähönen, Mika; Pérusse, Louis; Bouchard, Claude; Tönjes, Anke; Ida Chen, Yii-Der; Pennell, Craig E; Mori, Trevor A; Lieb, Wolfgang; Franke, Andre; Ohlsson, Claes; Mellström, Dan; Cho, Yoon Shin; Lee, Hyejin; Yuan, Jian-Min; Koh, Woon-Puay; Rhee, Sang Youl; Woo, Jeong-Taek; Heid, Iris M; Stark, Klaus J; Zimmermann, Martina E; Völzke, Henry; Homuth, Georg; Evans, Michele K; Zonderman, Alan B; Polasek, Ozren; Pasterkamp, Gerard; Hoefer, Imo E; Redline, Susan; Pahkala, Katja; Oldehinkel, Albertine J; Snieder, Harold; Biino, Ginevra; Schmidt, Reinhold; Schmidt, Helena; Bandinelli, Stefania; Dedoussis, George; Thanaraj, Thangavel Alphonse; Peyser, Patricia A; Kato, Norihiro; Schulze, Matthias B; Girotto, Giorgia; Böger, Carsten A; Jung, Bettina; Joshi, Peter K; Bennett, David A; De Jager, Philip L; Lu, Xiangfeng; Mamakou, Vasiliki; Brown, Morris; Caulfield, Mark J; Munroe, Patricia B; Guo, Xiuqing; Ciullo, Marina; Jonas, Jost B; Samani, Nilesh J; Kaprio, Jaakko; Pajukanta, Päivi; Tusié-Luna, Teresa; Aguilar-Salinas, Carlos A; Adair, Linda S; Bechayda, Sonny Augustin; de Silva, H Janaka; Wickremasinghe, Ananda R; Krauss, Ronald M; Wu, Jer-Yuarn; Zheng, Wei; den Hollander, Anneke I; Bharadwaj, Dwaipayan; Correa, Adolfo; Wilson, James G; Lind, Lars; Heng, Chew-Kiat; Nelson, Amanda E; Golightly, Yvonne M; Wilson, James F; Penninx, Brenda; Kim, Hyung-Lae; Attia, John; Scott, Rodney J; Rao, D C; Arnett, Donna K; Walker, Mark; Scott, Laura J; Koistinen, Heikki A; Chandak, Giriraj R; Mercader, Josep M; Villalpando, Clicerio Gonzalez; Orozco, Lorena; Fornage, Myriam; Tai, E Shyong; van Dam, Rob M; Lehtimäki, Terho; Chaturvedi, Nish; Yokota, Mitsuhiro; Liu, Jianjun; Reilly, Dermot F; McKnight, Amy Jayne; Kee, Frank; Jöckel, Karl-Heinz; McCarthy, Mark I; Palmer, Colin N A; Vitart, Veronique; Hayward, Caroline; Simonsick, Eleanor; van Duijn, Cornelia M; Jin, Zi-Bing; Lu, Fan; Hishigaki, Haretsugu; Lin, Xu; März, Winfried; Gudnason, Vilmundur; Tardif, Jean-Claude; Lettre, Guillaume; T Hart, Leen M; Elders, Petra J M; Rader, Daniel J; Damrauer, Scott M; Kumari, Meena; Kivimaki, Mika; van der Harst, Pim; Spector, Tim D; Loos, Ruth J F; Province, Michael A; Parra, Esteban J; Cruz, Miguel; Psaty, Bruce M; Brandslund, Ivan; Pramstaller, Peter P; Rotimi, Charles N; Christensen, Kaare; Ripatti, Samuli; Widén, Elisabeth; Hakonarson, Hakon; Grant, Struan F A; Kiemeney, Lambertus; de Graaf, Jacqueline; Loeffler, Markus; Kronenberg, Florian; Gu, Dongfeng; Erdmann, Jeanette; Schunkert, Heribert; Franks, Paul W; Linneberg, Allan; Jukema, J Wouter; Khera, Amit V; Männikkö, Minna; Jarvelin, Marjo-Riitta; Kutalik, Zoltan; Francesco, Cucca; Mook-Kanamori, Dennis O; Willems van Dijk, Ko; Watkins, Hugh; Strachan, David P; Grarup, Niels; Sever, Peter; Poulter, Neil; Huey-Herng Sheu, Wayne; Rotter, Jerome I; Dantoft, Thomas M; Karpe, Fredrik; Neville, Matt J; Timpson, Nicholas J; Cheng, Ching-Yu; Wong, Tien-Yin; Khor, Chiea Chuen; Li, Hengtong; Sabanayagam, Charumathi; Peters, Annette; Gieger, Christian; Hattersley, Andrew T; Pedersen, Nancy L; Magnusson, Patrik K E; Boomsma, Dorret I; de Geus, Eco J C; Cupples, L Adrienne; van Meurs, Joyce B J; Ikram, Arfan; Ghanbari, Mohsen; Gordon-Larsen, Penny; Huang, Wei; Kim, Young Jin; Tabara, Yasuharu; Wareham, Nicholas J; Langenberg, Claudia; Zeggini, Eleftheria; Tuomilehto, Jaakko; Kuusisto, Johanna; Laakso, Markku; Ingelsson, Erik; Abecasis, Goncalo; Chambers, John C; Kooner, Jaspal S; de Vries, Paul S; Morrison, Alanna C; Hazelhurst, Scott; Ramsay, Michèle; North, Kari E; Daviglus, Martha; Kraft, Peter; Martin, Nicholas G; Whitfield, John B; Abbas, Shahid; Saleheen, Danish; Walters, Robin G; Holmes, Michael V; Black, Corri; Smith, Blair H; Baras, Aris; Justice, Anne E; Buring, Julie E; Ridker, Paul M; Chasman, Daniel I; Kooperberg, Charles; Tamiya, Gen; Yamamoto, Masayuki; van Heel, David A; Trembath, Richard C; Wei, Wei-Qi; Jarvik, Gail P; Namjou, Bahram; Hayes, M Geoffrey; Ritchie, Marylyn D; Jousilahti, Pekka; Salomaa, Veikko; Hveem, Kristian; Åsvold, Bjørn Olav; Kubo, Michiaki; Kamatani, Yoichiro; Okada, Yukinori; Murakami, Yoshinori; Kim, Bong-Jo; Thorsteinsdottir, Unnur; Stefansson, Kari; Zhang, Jifeng; Chen, Y Eugene; Ho, Yuk-Lam; Lynch, Julie A; Tsao, Philip S; Chang, Kyong-Mi; Cho, Kelly; O'Donnell, Christopher J; Gaziano, John M; Wilson, Peter; Mohlke, Karen L; Frayling, Timothy M; Hirschhorn, Joel N; Kathiresan, Sekar; Boehnke, Michael; Million Veterans Program; Global Lipids Genetics Consortium; Struan Grant,; Natarajan, Pradeep; Sun, Yan V; Morris, Andrew P; Deloukas, Panos; Peloso, Gina; Assimes, Themistocles L; Willer, Cristen J; Zhu, Xiang; Brown, Christopher D
    A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.
  • Publication
    Cytokines and Inflammation in Meniere Disease.
    (2022-02-08) Frejo, Lidia; Lopez-Escamez, Jose Antonio
    Meniere disease (MD) is a rare set of conditions associated with the accumulation of endolymph in the cochlear duct and the vestibular labyrinth with a decrease of endocochlear potential. It is considered a chronic inflammatory disorder of the inner ear with a multifactorial origin. The clinical syndrome includes several groups of patients with a core phenotype: sensorineural hearing loss, episodes of vertigo, and tinnitus with a non-predictable course. Genetic factors and the innate immune response seem to play a central role in the pathophysiology of the condition. Autoimmune MD should be diagnosed if a patient fulfills the diagnostic criteria for MD and one of the following autoimmune disorders: autoimmune thyroid disease, psoriasis, autoimmune arthritis, ankylosing spondylitis, or systemic lupus erythematosus. We summarize the evidence to support autoimmune MD as an endophenotype in bilateral MD associated with the allelic variant rs4947296 and nuclear factor-kappa B (NF-κB)-mediated inflammation, the role of cytokines (particularly interleukin-1β and tumor necrosis factor-α) in defining a subset of patients with autoinflammation, and the potential role of cytokines as biomarkers to distinguish between patients with MD and vestibular migraine. Finally, we also introduce a list of potential drugs that could regulate the immune response in MD with potential for repurposing in clinical trials.
  • Publication
    Exchange of cellular components between platelets and tumor cells: impact on tumor cells behavior.
    (2022-02-07) Rodriguez-Martinez, Alba; Simon-Saez, Iris; Perales, Sonia; Garrido-Navas, Carmen; Russo, Alessandro; de Miguel-Perez, Diego; Puche-Sanz, Ignacio; Alaminos, Clara; Ceron, Jorge; Lorente, Jose A; Molina, Maria Pilar; Gonzalez, Coral; Cristofanilli, Massimo; Ortigosa-Palomo, Alba; Real, Pedro J; Rolfo, Christian; Serrano, María J
    Background: Platelets are active players in tumorigenesis, although the exact interactive mechanisms and their direct impact on tumor cells remain largely unknown. Methods: Bidirectional transference of lipids, proteins and RNA between platelets and tumor cells and its impact on tumor cell behavior and tumor process are analyzed in this work. Phenotypic, genetic and functional modifications induced by platelets were analyzed both in tumor cell lines and in circulating tumor cells (CTCs). Results: Data from these assays showed that platelets transferred structural components to tumor cells with higher efficiency than tumor cells to platelets (p = 0.001). This biological interplay occurred by direct contact, internalization or via extracellular vesicles. As a result, tumor cells acquired platelet markers (CD61 and CD42), showed decreased EpCAM, expressed epithelial-to-mesenchymal transition markers, and increased proliferation rates. Moreover, we were able to detect CD61 in CTCs from early and advanced prostate cancer. Conclusions: Our results demonstrated, for the first time, that platelets educate tumor cells by highly efficient transference of lipids, proteins and RNA through different mechanisms. These results suggest that tumor cells and CTCs might acquire highly dynamic and aggressive phenotypes due to platelets interaction including EMT, stem-like phenotype and high proliferative rates.
  • Publication
    Assessing the Impact of SARS-CoV-2 Lineages and Mutations on Patient Survival.
    (2022-08-27) Loucera, Carlos; Perez-Florido, Javier; Casimiro-Soriguer, Carlos S; Ortuño, Francisco M; Carmona, Rosario; Bostelmann, Gerrit; Martínez-González, L Javier; Muñoyerro-Muñiz, Dolores; Villegas, Román; Rodriguez-Baño, Jesus; Romero-Gomez, Manuel; Lorusso, Nicola; Garcia-León, Javier; Navarro-Marí, Jose M; Camacho-Martinez, Pedro; Merino-Diaz, Laura; Salazar, Adolfo de; Viñuela, Laura; The Andalusian Covid-Sequencing Initiative,; Lepe, Jose A; Garcia, Federico; Dopazo, Joaquin
    More than two years into the COVID-19 pandemic, SARS-CoV-2 still remains a global public health problem. Successive waves of infection have produced new SARS-CoV-2 variants with new mutations for which the impact on COVID-19 severity and patient survival is uncertain. A total of 764 SARS-CoV-2 genomes, sequenced from COVID-19 patients, hospitalized from 19th February 2020 to 30 April 2021, along with their clinical data, were used for survival analysis. A significant association of B.1.1.7, the alpha lineage, with patient mortality (log hazard ratio (LHR) = 0.51, C.I. = [0.14,0.88]) was found upon adjustment by all the covariates known to affect COVID-19 prognosis. Moreover, survival analysis of mutations in the SARS-CoV-2 genome revealed 27 of them were significantly associated with higher mortality of patients. Most of these mutations were located in the genes coding for the S, ORF8, and N proteins. This study illustrates how a combination of genomic and clinical data can provide solid evidence for the impact of viral lineage on patient survival.