Person: Anguita Mandly, Eduardo Luis
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First Name
Eduardo Luis
Last Name
Anguita Mandly
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Medicina
Department
Medicina
Area
Medicina
Identifiers
9 results
Search Results
Now showing 1 - 9 of 9
Item Biomarkers of stable and decompensated phases of heart failure with preserved ejection fraction(International journal of cardiology, 2022) Anguita Mandly, Eduardo Luis; Chaparro, Alberto; Candel González, Francisco Javier; Ramos Acosta, Carlos; Torrejón, María José; Llopis García, Guillermo; Suárez Cadenas, María del Mar; Matesanz, Mayra; González Del Castillo, Juan María; Martín Sánchez, Francisco Javier; Anguita, EduardoBackground Heart failure with preserved ejection fraction (HFpEF) is a disorder related to patient comorbidities and aging. Whether mitochondrial dysfunction is present during HFpEF decompensation versus the stable phase is largely unknown. The aim of the present study was to identify mitochondrial and cell metabolism blood biomarkers in older patients with acute and stable HFpEF. Methods Peripheral blood biomarkers were investigated in a group of eight to 12 patients aged 80–96 years and diagnosed with HFpEF first when they were in decompensated phase and then at least three months later in stable phase. Their data were compared to two control groups with an equal number of participants and sex proportions. One group was age matched and the other included individuals aged between 22 and 44 years. Results Decompensated patients experienced an increased mitochondrial superoxide production and mitochondrial mass, lower mitochondrial DNA copy number and LDHB expression, and higher lactate level compared to the stable stage. The stable phase was characterized by a sharp reduction in formate level. Multivariate analysis indicated that formate, lactate, and histidine can distinguish both of the HFpEF phases. Many of these parameters, including LDHB, lactate, formate, and mitochondrial mass, followed an age-related pattern, with acute HFpEF at its apex or nadir, suggesting that it represents an exacerbation of an aging-related process. Conclusions We identified distinct blood biomarkers of chronic and decompensated HFpEF phases. The data underlined the relationship between HFpEF and aging. These findings could be used to monitor patients and might be therapeutically targeted.Item Engraftment characterization of risk-stratified AML in NSGS mice(Blood advances, 2021) Díaz de la Guardia, Rafael; Anguita Mandly, Eduardo Luis; Menéndez, PabloAcute myeloid leukemia (AML) is the most common acute leukemia in adults. Disease heterogeneity is well documented, and patient stratification determines treatment decisions. Patient-derived xenografts (PDXs) from risk-stratified AML are crucial for studying AML biology and testing novel therapeutics. Despite recent advances in PDX modeling of AML, reproducible engraftment of human AML is primarily limited to high-risk (HR) cases, with inconsistent or very protracted engraftment observed for favorable-risk (FR) and intermediate-risk (IR) patients. We used NSGS mice to characterize the engraftment robustness/kinetics of 28 AML patient samples grouped according to molecular/cytogenetic classification and assessed whether the orthotopic coadministration of patient-matched bone marrow mesenchymal stromal cells (BM MSCs) improves AML engraftment. PDX event-free survival correlated well with the predictable prognosis of risk-stratified AML patients. The majority (85-94%) of the mice were engrafted in bone marrow (BM) independently of the risk group, although HR AML patients showed engraftment levels that were significantly superior to those of FR or IR AML patients. Importantly, the engraftment levels observed in NSGS mice by week 6 remained stable over time. Serial transplantation and long-term culture-initiating cell (LTC-IC) assays revealed long-term engraftment limited to HR AML patients, fitter leukemia-initiating cells (LICs) in HR AML samples, and the presence of AML LICs in the CD34− leukemic fraction, regardless of the risk group. Finally, orthotopic coadministration of patient-matched BM MSCs and AML cells was dispensable for BM engraftment levels but favored peripheralization of engrafted AML cells. This comprehensive characterization of human AML engraftment in NSGS mice offers a valuable platform for in vivo testing of targeted therapies in risk-stratified AML patient samples.Item e14a2 Transcript Favors Treatment-Free Remission in Chronic Myeloid Leukemia When Associated with Longer Treatment with Tyrosine Kinase Inhibitors and Sustained Deep Molecular Response(Journal of clinical medicine, 2024) Marcé, Sílvia; Escribano Serrat, Silvia; Anguita Mandly, Eduardo Luis; Zamora, Lurdese13a2 and e14a2 are the most frequent transcript types of the BCR::ABL1 fusion gene in chronic myeloid leukemia (CML). The current goal with tyrosine kinase inhibitors (TKI) is to achieve sustained deep molecular response (DMR) in order to discontinue TKI treatment and remain in the so-called treatment-free remission (TFR) phase, but biological factors associated with these goals are not well established. This study aimed to determine the effect of transcript type on TFR in patients receiving frontline treatment with imatinib (IM) or second-generation TKI (2G-TKI). Patients treated at least 119 months with IM presented less post-discontinuation relapse than those that discontinued IM before 119 months (p = 0.005). In addition, cases with the e14a2 transcript type treated at least 119 months with IM presented a better TFR (p = 0.024). On the other hand, the type of transcript did not affect the cytogenetic or molecular response in 2G-TKI treated patients; however, the use of 2G-TKI may be associated with higher and earlier DMR in patients with the e14a2 transcript.Item An NMR-Based Model to Investigate the Metabolic Phenoreversion of COVID-19 Patients throughout a Longitudinal Study(Metabolites, 2022) Gil Redondo, Rubén; Ramos Acosta, Carlos; Anguita Mandly, Eduardo Luis; Millet, OscarAfter SARS-CoV-2 infection, the molecular phenoreversion of the immunological response and its associated metabolic dysregulation are required for a full recovery of the patient. This process is patient-dependent due to the manifold possibilities induced by virus severity, its phylogenic evolution and the vaccination status of the population. We have here investigated the natural history of COVID-19 disease at the molecular level, characterizing the metabolic and immunological phenoreversion over time in large cohorts of hospitalized severe patients (n = 886) and non-hospitalized recovered patients that self-reported having passed the disease (n = 513). Non-hospitalized recovered patients do not show any metabolic fingerprint associated with the disease or immune alterations. Acute patients are characterized by the metabolic and lipidomic dysregulation that accompanies the exacerbated immunological response, resulting in a slow recovery time with a maximum probability of around 62 days. As a manifestation of the heterogeneity in the metabolic phenoreversion, age and severity become factors that modulate their normalization time which, in turn, correlates with changes in the atherogenesis-associated chemokine MCP-1. Our results are consistent with a model where the slow metabolic normalization in acute patients results in enhanced atherosclerotic risk, in line with the recent observation of an elevated number of cardiovascular episodes found in post-COVID-19 cohorts.Item The ETO2 transcriptional cofactor maintains acute leukemia by driving a MYB/EP300‐dependent stemness program(Hemasphere, 2024) Fagnan, Alexandre; Anguita Mandly, Eduardo Luis; Mercher, ThomasTranscriptional cofactors of the ETO family are recurrent fusion partners in acute leukemia. We characterized the ETO2 regulome by integrating transcriptomic and chromatin binding analyses in human erythroleukemia xenografts and controlled ETO2 depletion models. We demonstrate that beyond its well‐established repressive activity, ETO2 directly activates transcription of MYB, among other genes. The ETO2‐activated signature is associated with a poorer prognosis in erythroleukemia but also in other acute myeloid and lymphoid leukemia subtypes. Mechanistically, ETO2 colocalizes with EP300 and MYB at enhancers supporting the existence of an ETO2/MYB feedforward transcription activation loop (e.g., on MYB itself). Both small‐molecule and PROTAC‐mediated inhibition of EP300 acetyltransferases strongly reduced ETO2 protein, chromatin binding, and ETO2‐activated transcripts. Taken together, our data show that ETO2 positively enforces a leukemia maintenance program that is mediated in part by the MYB transcription factor and that relies on acetyltransferase cofactors to stabilize ETO2 scaffolding activity.Item Tigecycline Opposes Bortezomib Effect on Myeloma Cells Decreasing Mitochondrial Reactive Oxygen Species Production(International journal of molecular sciences, 2024) Ramos Acosta, Carlos; Huerta Pantoja, Laura; Salazar Hidalgo, Milton Eduardo; Mayol, Elsa; Jiménez Vega, Selene; García Peña, Pablo; Jordi Cruz, Jenifeer; Baquero, Cristina; Porras Gallo, María Almudena; Íñigo Rodríguez, Belén; Benavente Cuesta, Celina; Candel González, Francisco Javier; Anguita Mandly, Eduardo LuisMultiple myeloma is an incurable plasma cell malignancy. Most patients end up relapsing and developing resistance to antineoplastic drugs, like bortezomib. Antibiotic tigecycline has activity against myeloma. This study analyzed tigecycline and bortezomib combination on cell lines and plasma cells from myeloma patients. Apoptosis, autophagic vesicles, mitochondrial mass, mitochondrial superoxide, cell cycle, and hydrogen peroxide were studied by flow cytometry. In addition, mitochondrial antioxidants and electron transport chain complexes were quantified by reverse transcription real-time PCR (RT-qPCR) or western blot. Cell metabolism and mitochondrial activity were characterized by Seahorse and RT-qPCR. We found that the addition of tigecycline to bortezomib reduces apoptosis in proportion to tigecycline concentration. Supporting this, the combination of both drugs counteracts bortezomib in vitro individual effects on the cell cycle, reduces autophagy and mitophagy markers, and reverts bortezomib-induced increase in mitochondrial superoxide. Changes in mitochondrial homeostasis and MYC upregulation may account for some of these findings. These data not only advise to avoid considering tigecycline and bortezomib combination for treating myeloma, but caution on the potential adverse impact of treating infections with this antibiotic in myeloma patients under bortezomib treatment.Item Specific Cellular and Humoral Immune Responses to the Neoantigen RBD of SARS-CoV-2 in Patients with Primary and Secondary Immunodeficiency and Healthy Donors(Biomedicines, 2023) Mohamed, Kauzar Mohamed; Guevara Hoyer, Kissy; Jiménez García, Carlos; García Bravo, Laura; Rodríguez de la Peña, Antonia; Mediero Valeros, Beatriz; Cañizares Velázquez, Cristina; Culebras López, Esther; Cabello, Noemí; Estrada Pérez, Vicente; Fernández Arquero, Miguel; Ocaña, Alberto; Delgado-Iribarren García-Campero, Albert; Martínez-Novillo González, Mercedes; Bolaños, Estefanía; Anguita Mandly, Eduardo Luis; Peña Cortijo, Ascensión; Benavente Cuesta, Celina; Benítez Fuentes, Javier David; Pérez Segura, Pedro; Sánchez Ramón, Silvia MaríaPatients with antibody deficiency disorders, such as primary immunodeficiency (PID) or secondary immunodeficiency (SID) to B-cell lymphoproliferative disorder (B-CLPD), are two groups vulnerable to developing the severe or chronic form of coronavirus disease caused by SARS-CoV-2 (COVID-19). The data on adaptive immune responses against SARS-CoV-2 are well described in healthy donors, but still limited in patients with antibody deficiency of a different cause. Herein, we analyzed spike-specific IFN-γ and anti-spike IgG antibody responses at 3 to 6 months after exposure to SARS-CoV-2 derived from vaccination and/or infection in two cohorts of immunodeficient patients (PID vs. SID) compared to healthy controls (HCs). Pre-vaccine anti-SARS-CoV-2 cellular responses before vaccine administration were measured in 10 PID patients. Baseline cellular responses were detectable in 4 out of 10 PID patients who had COVID-19 prior to vaccination, perceiving an increase in cellular responses after two-dose vaccination (p < 0.001). Adequate specific cellular responses were observed in 18 out of 20 (90%) PID patients, in 14 out of 20 (70%) SID patients and in 74 out of 81 (96%) HCs after vaccination (and natural infection in some cases). Specific IFN-γ response was significantly higher in HC with respect to PID (1908.5 mUI/mL vs. 1694.1 mUI/mL; p = 0.005). Whereas all SID and HC patients mounted a specific humoral immune response, only 80% of PID patients showed positive anti-SARS-CoV-2 IgG. The titer of anti-SARS-CoV-2 IgG was significantly lower in SID compared with HC patients (p = 0.040), without significant differences between PID and HC patients (p = 0.123) and between PID and SID patients (p =0.683). High proportions of PID and SID patients showed adequate specific cellular responses to receptor binding domain (RBD) neoantigen, with a divergence between the two arms of the adaptive immune response in PID and SID patients. We also focused on the correlation of protection of positive SARS-CoV-2 cellular response to omicron exposure: 27 out of 81 (33.3%) HCs referred COVID-19 detected by PCR or antigen test, 24 with a mild course, 1 with moderate symptoms and the remaining 2 with bilateral pneumonia that were treated in an outpatient basis. Our results might support the relevance of these immunological studies to determine the correlation of protection with severe disease and for deciding the need for additional boosters on a personalized basis. Follow-up studies are required to evaluate the duration and variability in the immune response to COVID-19 vaccination or infection.Item A Novel Bead-Capture Nanopore Sequencing Method for Large Structural Rearrangement Detection in Cancer(The Journal of molecular diagnostics, 2022) Fisher, Chloe L.; Dillon, Richard; Anguita Mandly, Eduardo Luis; Morris Rosendahl, Deborah J.; Awan, Ali R.Rapid, cost-effective genomic stratification of structural rearrangements in cancer is often of vital importance when determining treatment; however, existing diagnostic cytogenetic and molecular testing fails to deliver the required speed when deployed at scale. Next-generation sequencing-based methods are widely used, but these can lack sensitivity and require batching of samples to be cost-effective, with long turnaround times. Here we present a novel method for rearrangement detection from genomic DNA based on third-generation long-read sequencing that overcomes these time and cost issues. The utility of this approach for the genomic stratification of patients with acute myeloid leukemia is shown based on detection of four of the most prevalent structural rearrangements. The method not only determines the precise genomic breakpoint for each expected rearrangement but also discovers and validates novel translocations in one-third of the tested samples, 80% of which involve known oncogenes. This method may prove to be a powerful tool for the diagnosis, genomic stratification, and characterization of cancers.Item Free triiodothyronine levels and age influences the metabolic profile and COVID-19 severity parameters in euthyroid and levothyroxine-treated patients(Frontiers in Endocrinology, 2022) Amich, Inés; Anguita Mandly, Eduardo Luis; Escribano Serrat, Silvia; Álvarez, Cristina; García, Verónica; Bello, Rocío; Peña Pedrosa, José Alberto; Torrejón, María José; Martín Sánchez, Francisco Javier; Alemany, SusanaMetabolic reprogramming is required to fight infections and thyroid hormones are key regulators of metabolism. We have analyzed in hospitalized COVID-19 patients: 40 euthyroid and 39 levothyroxine (LT4)-treated patients in the ward and 29 euthyroid and 9 LT4-treated patients in the intensive care unit (ICU), the baseline characteristics, laboratory data, thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), the FT3/FT4 ratio, 11 antiviral cytokines and 74 metabolomic parameters. No evidence for significant differences between euthyroid and LT4-treated patients were found in the biochemical, metabolomic and cytokines parameters analyzed. Only TSH (p=0.009) and ferritin (p=0.031) showed significant differences between euthyroid and LT4-treated patients in the ward, and TSH (p=0.044) and FT4 (p=0.012) in the ICU. Accordingly, severity and mortality were similar in euthyroid and LT4-treated patients. On the other hand, FT3 was negatively related to age (p=0.012), independently of sex and body mass index in hospitalized COVID-19 patients. Patients with low FT3 and older age showed a worse prognosis and higher levels of the COVID-19 severity markers IL-6 and IL-10 than patients with high FT3. IL-6 negatively correlated with FT3 (p=0.023) independently of age, body mass index and sex, whereas IL-10 positively associated with age (p=0.035) independently of FT3, body mass index and sex. A metabolomic cluster of 6 parameters defined low FT3 ward patients. Two parameters, esterified cholesterol (p=4.1x10-4) and small HDL particles (p=6.0x10-5) correlated with FT3 independently of age, body mass index and sex, whereas 3-hydroxybutyrate (p=0.010), acetone (p=0.076), creatinine (p=0.017) and high-density-lipoprotein (HDL) diameter (p=8.3x10-3) were associated to FT3 and also to age, with p-values of 0.030, 0.026, 0.017 and 8.3x10-3, respectively. In conclusion, no significant differences in FT3, cytokines, and metabolomic profile, or in severity and outcome of COVID-19, were found during hospitalization between euthyroid patients and hypothyroid patients treated with LT4. In addition, FT3 and age negatively correlate in COVID-19 patients and parameters that predict poor prognosis were associated with low FT3, and/or with age. A metabolomic cluster indicative of a high ketogenic profile defines non-critical hospitalized patients with low FT3 levels.