Pineda-Lucena, A. (Antonio)
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- Protein biomarkers in lung cancer screening: technical considerations and feasibility assessment(Elsevier, 2024) Seijo, L. (Luis); Calle-Arroyo, C. (Carlos) de la; Pineda-Lucena, A. (Antonio); Detterbeck, F. (Frank); Bernasconi-Bisio, F. (Franco); Johansson, M. (Mattias); Montuenga-Badia, L.M. (Luis M.); Orive-Mauleón, D. (Daniel); Hung, J.R. (Rayjean); Valencia, K. (Karmele); Echepare, M. (Mirari); Robbins, H.A. (Hilary); Fernandez-Sanmamed, M. (Miguel)Lung cancer remains the leading cause of cancer-related deaths worldwide, mainly due to late diagnosis and the presence of metastases. Several countries around the world have adopted nation-wide LDCT-based lung cancer screening that will benefit patients, shifting the stage at diagnosis to earlier stages with more therapeutic options. Biomarkers can help to optimize the screening process, as well as refine the TNM stratification of lung cancer patients, providing information regarding prognostics and recommending management strategies. Moreover, novel adjuvant strategies will clearly benefit from previous knowledge of the potential aggressiveness and biological traits of a given early-stage surgically resected tumor. This review focuses on proteins as promising biomarkers in the context of lung cancer screening. Despite great efforts, there are still no successful examples of biomarkers in lung cancer that have reached the clinics to be used in early detection and early management. Thus, the field of biomarkers in early lung cancer remains an evident unmet need. A more specific objective of this review is to present an up-to-date technical assessment of the potential use of protein biomarkers in early lung cancer detection and management. We provide an overview regarding the benefits, challenges, pitfalls and constraints in the development process of protein-based biomarkers. Additionally, we examine how a number of emerging protein analytical technologies may contribute to the optimization of novel robust biomarkers for screening and effective management of lung cancer.
- Polycythemia vera and essential thrombocythemia patients exhibit unique serum metabolic profiles compared to healthy individuals and secondary thrombocytosis patients(2021) Martínez-López, J. (Joaquín); Pineda-Lucena, A. (Antonio); Albors-Vaquer, A. (A.); Besses, C. (Carles); Gómez-Cebrián, N. (Nuria); Rojas-Benedicto, A. (Ayelén); Bellosillo, B. (Beatriz); Puchades-Carrasco, L. (Leonor)Simple Summary Current diagnosis of myeloproliferative neoplasms (MPNs), including polycythemia vera (PV) and essential thrombocythemia (ET), is controversial due to limitations associated with the lack of reproducibility, subjectivity and the presence of common somatic mutations in the driver genes. Metabolomics represents a powerful approach to identify altered metabolites that can differentiate between disease status at the time of diagnosis. The objective of this study was to characterize the serum metabolic profile of MPNs patients (PV and ET) and compare it with healthy controls (HC) and secondary thrombocytosis (ST) patients. The analysis revealed metabolites following similar trends between PV and ET patients, as well as unique significant differences in the serum metabolite levels of MNPs patients compared to HC and ST patients. These results could contribute to better differentiate patients with these diseases from HC and ST patients. Most common myeloproliferative neoplasms (MPNs) include polycythemia vera (PV) and essential thrombocythemia (ET). Accurate diagnosis of these disorders remains a clinical challenge due to the lack of specific clinical or molecular features in some patients enabling their discrimination. Metabolomics has been shown to be a powerful tool for the discrimination between different hematological diseases through the analysis of patients' serum metabolic profiles. In this pilot study, the potential of NMR-based metabolomics to characterize the serum metabolic profile of MPNs patients (PV, ET), as well as its comparison with the metabolic profile of healthy controls (HC) and secondary thrombocytosis (ST) patients, was assessed. The metabolic profile of PV and ET patients, compared with HC, exhibited higher levels of lysine and decreased levels of acetoacetic acid, glutamate, polyunsaturated fatty acids (PUFAs), scyllo-inositol and 3-hydroxyisobutyrate. Furthermore, ET patients, compared with HC and ST patients, were characterized by decreased levels of formate, N-acetyl signals from glycoproteins (NAC) and phenylalanine, while the serum profile of PV patients, compared with HC, showed increased concentrations of lactate, isoleucine, creatine and glucose, as well as lower levels of choline-containing metabolites. The overall analysis revealed significant metabolic alterations mainly associated with energy metabolism, the TCA cycle, along with amino acid and lipid metabolism. These results underscore the potential of metabolomics for identifying metabolic alterations in the serum of MPNs patients that could contribute to improving the clinical management of these diseases.
- Searching for peptide inhibitors of T regulatory cell activity by targeting specific domains of FOXP3 transcription factor(2021) Pineda-Lucena, A. (Antonio); Lozano-Moreda, T. (Teresa); Oyarzabal, J. (Julen); Martil-Otal, C. (Celia); Casares, N. (Noelia); Gorraiz, M. (Marta); Ruiz-Guillen, M. (Marta); Belsue, V. (Virginia); Parker, J. (Jonathan); Anega, B. (Blanca); Lasarte, J.J. (Juan José)(1) Background: The ability of cancer cells to evade the immune system is due in part to their capacity to induce and recruit T regulatory cells (Tregs) to the tumor microenvironment. Strategies proposed to improve antitumor immunity by depleting Tregs generally lack specificity and raise the possibility of autoimmunity. Therefore, we propose to control Tregs by their functional inactivation rather than depletion. Tregs are characterized by the expression of the Forkhead box protein 3 (FOXP3) transcription factor, which is considered their "master regulator". Its interaction with DNA is assisted primarily by its interaction with other proteins in the so-called "Foxp3 interactome", which elicits much of the characteristic Treg cell transcriptional signature. We speculated that the disruption of such a protein complex by using synthetic peptides able to bind Foxp3 might have an impact on the functionality of Treg cells and thus have a therapeutic potential in cancer treatment. (2) Methods: By using a phage-displayed peptide library, or short synthetic peptides encompassing Foxp3 fragments, or by studying the crystal structure of the Foxp3:NFAT complex, we have identified a series of peptides that are able to bind Foxp3 and inhibit Treg activity. (3) Results: We identified some peptides encompassing fragments of the leuzin zipper or the C terminal domain of Foxp3 with the capacity to inhibit Treg activity in vitro. The acetylation/amidation of linear peptides, head-to-tail cyclization, the incorporation of non-natural aminoacids, or the incorporation of cell-penetrating peptide motifs increased in some cases the Foxp3 binding capacity and Treg inhibitory activity of the identified peptides. Some of them have shown antitumoral activity in vivo. (4) Conclusions: Synthetic peptides constitute an alternative to inhibit Foxp3 protein-protein interactions intracellularly and impair Treg immunosuppressive activity. These peptides might be considered as potential hit compounds on the design of new immunotherapeutic approaches against cancer.
- Trimethylamine N-oxide (TMAO) drives insulin resistance and cognitive deficiencies in a senescence accelerated mouse model(Elsevier, 2022) Pineda-Lucena, A. (Antonio); Puerta, E. (Elena); Ludwig, I.A. (Iziar Amaia); Ramirez, M.J. (María Javier); Milagro-Yoldi, F.I. (Fermín Ignacio); Solas, M. (Maite); Janeiro-Arenas, M.H. (Manuel Humberto); Lanz, M. (María)It has been established that ageing is the major risk factor for cognitive deficiency and it is becoming increasingly evident that insulin resistance is another factor. Biological plausibility for a link between insulin resistance and dementia is relevant for understanding disease etiology, and to form bases for prevention efforts to decrease disease burden. In the present study, peripheral and central insulin resistance was found in SAMP8 mice (aging mouse model) accompanied by cognitive deficiencies. Furthermore, a marked peripheral inflammatory state was observed in SAMP8 mice, followed by neuroinflammation that could be due to a higher cytokine leaking into the brain across an aging-disrupted blood brain barrier. Moreover, aging-induced gut dysbiosis produces higher TMAO that could also contribute to the peripheral and central inflammatory tone as well as to the cognitive deficiencies observed in SAMP8 mice. All those alterations were reversed by DMB, a treatment that decreases TMAO levels. Data obtained from this project suggest that microbial dysbiosis and increased TMAO secretion could be a key link between aging, insulin resistance and dementia. Thus, pharmacological intervention that leads to decreased TMAO levels, such as DMB, could open a new avenue for the future treatment of neurodegenerative diseases.
- Metabolic footprint of aging and obesity in red blood cells(2021) Pineda-Lucena, A. (Antonio); Lamas-Domingo, R. (Rubén); Palomino-Schatzlein, M. (Martina); Domingo-Ortí, I. (Inés); Hernández, C. (Cristina); Ciudin, A. (Andreea); Herance, J.R. (José Raúl)Aging is a physiological process whose underlying mechanisms are still largely unknown. The study of the biochemical transformations associated with aging is crucial for understanding this process and could translate into an improvement of the quality of life of the aging population. Red blood cells (RBCs) are the most abundant cells in humans and are involved in essential functions that could undergo different alterations with age. The present study analyzed the metabolic alterations experienced by RBCs during aging, as well as the influence of obesity and gender in this process. To this end, the metabolic profile of 83 samples from healthy and obese patients was obtained by Nuclear Magnetic Resonance spectroscopy. Multivariate statistical analysis revealed differences between Age-1 (<= 45) and Age-2 ( 45) subgroups, as well as between BMI-1 (<30) and BMI2 (>= 30) subgroups, while no differences were associated with gender. A general decrease in the levels of amino acids was detected with age, in addition to metabolic alterations of glycolysis, the pentose phosphate pathway, nucleotide metabolism, glutathione metabolism and the Luebering-Rapoport shunt. Obesity also had an impact on the metabolomics profile of RBCs; sometimes mimicking the alterations induced by aging, while, in other cases, its influence was the opposite, suggesting these changes could counteract the adaptation of the organism to senescence.
- Identification and experimental validation of druggable epigenetic targets in hepatoblastoma(Elsevier, 2023) Indersie, E. (Emilie); Latasa, M.U. (María Ujué); Berraondo, P. (Pedro); Corrales, F.J. (Fernando José); Berasain, C. (Carmen); Arechederra, M. (María); Domingo-Sàbat, M. (Montserrat); Pineda-Lucena, A. (Antonio); Sancho-Bru, P. (Pau); Zanatto, L. (Laura); Armengol, C. (Carolina); Uriarte, I. (Iker); Ciordia, S. (Sergio); Avila, M.A. (Matías Antonio); Alaggio, R. (Rita); Alonso, C. (Cristina); Sangro, B. (Bruno); García-Fernandez-Barrena, M. (Maite); Herranz, J.M. (José M.); Cairo, S. (Stefano); García-Marin, J.J. (Jose Juan); Francalanci, P. (Paola); Prosper-Cardoso, F. (Felipe); Claveria-Cabello, A. (Alex); Martinez-Chantar, M.L. (María Luz); Zucman-Rossi, J. (Jessica)Background & Aims: Hepatoblastoma (HB) is the most frequent childhood liver cancer. Patients with aggressive tumors have limited therapeutic options; therefore, a better understanding of HB pathogenesis is needed to improve treatment. HBs have a very low mutational burden; however, epigenetic alterations are increasingly recognized. We aimed to identify epigenetic regulators consistently dysregulated in HB and to evaluate the therapeutic efficacy of their targeting in clinically relevant models. Methods: We performed a comprehensive transcriptomic analysis of 180 epigenetic genes. Data from fetal, pediatric, adult, peritumoral (n = 72) and tumoral (n = 91) tissues were integrated. Selected epigenetic drugs were tested in HB cells. The most relevant epigenetic target identified was validated in primary HB cells, HB organoids, a patient-derived xenograft model, and a genetic mouse model. Transcriptomic, proteomic and metabolomic mechanistic analyses were performed. Results: Altered expression of genes regulating DNA methylation and histone modifications was consistently observed in association with molecular and clinical features of poor prognosis. The histone methyltransferase G9a was markedly upregulated in tumors with epigenetic and transcriptomic traits of increased malignancy. Pharmacological targeting of G9a significantly inhibited growth of HB cells, organoids and patient-derived xenografts. Development of HB induced by oncogenic forms of b-catenin and YAP1 was ablated in mice with hepatocyte-specific deletion of G9a. We observed that HBs undergo significant transcriptional rewiring in genes involved in amino acid metabolism and ribosomal biogenesis. G9a inhibition counteracted these pro-tumorigenic adaptations. Mechanistically, G9a targeting potently repressed the expression of c-MYC and ATF4, master regulators of HB metabolic reprogramming. Conclusions: HBs display a profound dysregulation of the epigenetic machinery. Pharmacological targeting of key epigenetic effectors exposes metabolic vulnerabilities that can be leveraged to improve the treatment of these patients.
- CM-352 Efficacy in a mouse model of anticoagulant-associated intracranial hemorrhage(Thieme, 2022) Navarro-Oviedo, M. (Manuel); Paramo, J.A. (José Antonio); Pineda-Lucena, A. (Antonio); Zandio, B. (Beatriz); Hermida, J. (José); Orbe, J. (Josune); Rodriguez, J.A. (José Antonio); Muñoz, R. (Roberto); Oyarzabal, J. (Julen); Lecumberri, R. (Ramón); Roncal, C. (Carmen); Marta-Enguita, J. (Juan)Background: Intracranial hemorrhage (ICH) is one of the major devastating complications of anticoagulation. Matrix metalloproteinase (MMP) inhibition has been proposed as a novel pharmacological approach for ICH treatment. Objectives: We evaluated the effects of CM-352 (MMP-fibrinolysis inhibitor) in an experimental ICH model associated with oral anticoagulants as compared with clinically used prothrombin complex concentrate (PCC). Methods: ICH was induced by collagenase injection into the striatum of wild type (C57BL/6J) anticoagulated mice (warfarin or rivaroxaban) and Mmp10 -/- mice. Hematoma volume and neurological deficits were measured 24 hours later by diaminobenzidine staining and different behavioral tests. Circulating plasminogen activator inhibitor-1 (PAI-1) activity and interleukin-6 (IL-6) were measured in plasma samples and local inflammation was assessed by neutrophil infiltration. Finally, fibrinolytic effects of MMP-10 and rivaroxaban were evaluated by thromboelastometry and thrombin-activatable fibrinolysis inhibitor (TAFI) activation assays. Results: Only PCC reduced hemorrhage volume and improved functional outcome in warfarin-ICH, but both PCC and CM-352 treatments diminished hemorrhage volume (46%, p < 0.01 and 64%, p < 0.001, respectively) and ameliorated functional outcome in rivaroxaban-ICH. We further demonstrated that CM-352, but not PCC, decreased neutrophil infiltration in the hemorrhage area at 24 hours. The effect of CM-352 could be related to MMP-10 inhibition since Mmp10 -/- mice showed lower hemorrhage volume, better neurological score, reduced IL-6 levels and neutrophil infiltration, and increased PAI-1 after experimental ICH. Finally, we found that CM-352 reduced MMP-10 and rivaroxaban-related fibrinolytic effects in thromboelastometry and TAFI activation. Conclusion: CM-352 treatment, by diminishing MMPs and rivaroxaban-associated fibrinolytic effects, might be a novel antihemorrhagic strategy for rivaroxaban-associated ICH.
- Splicing factor SLU7 prevents oxidative stress-mediated hepatocyte nuclear factor 4α degradation, preserving hepatic differentiation and protecting from liver damage(Wiley, 2021) Latasa, M.U. (María Ujué); Corrales, F.J. (Fernando José); Berasain, C. (Carmen); Arechederra, M. (María); Pineda-Lucena, A. (Antonio); Uriarte, I. (Iker); Avila, M.A. (Matías Antonio); García-Ruiz, C. (Carmen); Azkona, M.T. (María Teresa); Sangro, B. (Bruno); Fernández-Checa, J.C. (José C.); Esquivel, A. (Argitxu); Raquel; Recalde, M. (Miriam); Gárate-Rascón, M. (María); García-Fernández-de-Barrena, M. (Maite); Elizalde, M. (María); Bilbao, I. (Idoia); Jiménez-Andrés, M. (Maddalen)Background and aims: Hepatocellular dedifferentiation is emerging as an important determinant in liver disease progression. Preservation of mature hepatocyte identity relies on a set of key genes, predominantly the transcription factor hepatocyte nuclear factor 4α (HNF4α) but also splicing factors like SLU7. How these factors interact and become dysregulated and the impact of their impairment in driving liver disease are not fully understood. Approach and results: Expression of SLU7 and that of the adult and oncofetal isoforms of HNF4α, driven by its promoter 1 (P1) and P2, respectively, was studied in diseased human and mouse livers. Hepatic function and damage response were analyzed in wild-type and Slu7-haploinsufficient/heterozygous (Slu7+/- ) mice undergoing chronic (CCl4 ) and acute (acetaminophen) injury. SLU7 expression was restored in CCl4 -injured mice using SLU7-expressing adeno-associated viruses (AAV-SLU7). The hepatocellular SLU7 interactome was characterized by mass spectrometry. Reduced SLU7 expression in human and mouse diseased livers correlated with a switch in HNF4α P1 to P2 usage. This response was reproduced in Slu7+/- mice, which displayed increased sensitivity to chronic and acute liver injury, enhanced oxidative stress, and marked impairment of hepatic functions. AAV-SLU7 infection prevented liver injury and hepatocellular dedifferentiation. Mechanistically we demonstrate a unique role for SLU7 in the preservation of HNF4α1 protein stability through its capacity to protect the liver against oxidative stress. SLU7 is herein identified as a key component of the stress granule proteome, an essential part of the cell's antioxidant machinery. Conclusions: Our results place SLU7 at the highest level of hepatocellular identity control, identifying SLU7 as a link between stress-protective mechanisms and liver differentiation. These findings emphasize the importance of the preservation of hepatic functions in the protection from liver injury.
- A surface plasmon resonance based approach for measuring response to pneumococcal vaccine(2021) Garrido, J.M.; Pineda-Lucena, A. (Antonio); López-Hontangas, J.L. (José Luis); Orti-Pérez, L. (Leticia); Meyer-García, M.C. (María del Carmen); Lloret-Sos, C. (Carmina); Gil‑Brusola, A. (Ana); Garrido-Jareño, M. (Marta); Pemán-García, J. (Javier); Mollar‑Maseres, J. (Joan); Puchades-Carrasco, L. (Leonor); Sahuquillo-Arce, J.M. (José Miguel)Incidence of pneumococcal disease has increased worldwide in recent years. Response to pneumococcal vaccine is usually measured using the multiserotype enzyme-linked immunosorbent assay (ELISA) pneumococcal test. However, this approach presents several limitations. Therefore, the introduction of new and more robust analytical approaches able to provide information on the efficacy of the pneumococcal vaccine would be very beneficial for the clinical management of patients. Surface plasmon resonance (SPR) has been shown to offer a valuable understanding of vaccines' properties over the last years. The aim of this study is to evaluate the reliability of SPR for the anti-pneumococcal capsular polysaccharides (anti-PnPs) IgGs quantification in vaccinated. Fast protein liquid chromatography (FPLC) was used for the isolation of total IgGs from serum samples of vaccinated patients. Binding-SPR assays were performed to study the interaction between anti-PnPs IgGs and PCV13. A robust correlation was found between serum levels of anti-PnPs IgGs, measured by ELISA, and the SPR signal. Moreover, it was possible to correctly classify patients into "non-responder", "responder" and "high-responder" groups according to their specific SPR PCV13 response profiles. SPR technology provides a valuable tool for reliably characterize the interaction between anti-PnPs IgGs and PCV13 in a very short experimental time.
- Photodynamic nasal SARS-CoV-2 decolonization shortens infectivity and influences specific T-Cell responses.(Frontiers, 2023) Moreno-Galarraga, L. (Laura); Martin-Navarro, L. (Loreto); González-Aseguinolaza, G. (Gloria); Muñoz-Rodríguez, N. (Natalia); Pineda-Lucena, A. (Antonio); Olagüe, C. (Cristina); Pina-Sanchez, M. (Manuel); Camps, G. (Gracian); Rua, M. (Marta); Smerdou, C. (Cristian); Pozo, J.L. (José Luis) del; Pozuelo, M. (Marta); Zuaznabar, J. (Jon); Rodriguez, J.A. (José Antonio); Carmona-Torre, F. (Francisco de A.); Fernandez-Montero, A. (Alejandro); Zazpe, J. (Jon); Reina, G. (Gabriel); Kolenda, J. (Jack); Marchese, F.P. (Francesco P.); Quiroga, J. (Jorge); Martínez-Fernández, M. (Maria); Argemí, J. (Josepmaria); Pastrana, M. (Marta); Maestro, S. (Sheila)Background: The main objective was to evaluate the efficacy of intranasal photodynamic therapy (PDT) in SARS-CoV-2 mildly symptomatic carriers on decreasing the infectivity period. SARS-CoV-2-specific immune-stimulating effects and safety were also analysed. Methods: We performed a randomized, placebo-controlled, clinical trial in a tertiary hospital (NCT05184205). Patients with a positive SARS-CoV-2 PCR in the last 48 hours were recruited and aleatorily assigned to PDT or placebo. Patients with pneumonia were excluded. Participants and investigators were masked to group assignment. The primary outcome was the reduction in in vitro infectivity of nasopharyngeal samples at days 3 and 7. Additional outcomes included safety assessment and quantification of humoral and T-cell immune-responses. Findings: Patients were recruited between December 2021 and February 2022. Most were previously healthy adults vaccinated against COVID-19 and most carried Omicron variant. 38 patients were assigned to placebo and 37 to PDT. Intranasal PDT reduced infectivity at day 3 post-treatment when compared to placebo with a b-coefficient of -812.2 (CI95%= -478660 – -1.3, p<0.05) infectivity arbitrary units. The probability of becoming PCR negative (ct>34) at day 7 was higher on the PDT-group, with an OR of 0.15 (CI95%=0.04-0.58). There was a decay in anti-Spike titre and specific SARS-CoV-2 T cell immunity in the placebo group 10 and 20 weeks after infection, but not in the PDT-group. No serious adverse events were reported. Interpretation: Intranasal-PDT is safe in pauci-symptomatic COVID-19 patients, it reduces SARS-CoV-2 infectivity and decelerates the decline SARS-CoV-2 specific immune-responses.