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Publication Effects of the Ser326Cys Polymorphism in the DNA Repair OGG1 Gene on Cancer, Cardiovascular, and All-Cause Mortality in the PREDIMED Study: Modulation by Diet(Elsevier, 2018-04) Corella, Dolores; Ramirez-Sabio, Judith B; Coltell, Oscar; Ortega-Azorin, Carolina; Estruch, Ramon; Martinez-Gonzalez, Miguel A; Salas-Salvado, Jordi; Sorli, Jose V; Castaner, Olga; Aros, Fernando; Garcia-Corte, Franscisco J; Serra-Majem, Lluis; Gomez-Gracia, Enrique; Fiol Sala, Miquel; Pinto, Xavier; Saez, Guillermo T; Toledo, Estefanía; Basora, Josep; Fito, Montserrat; Cofan, Montserrat; Ros, Emilio; Ordovas, Jose MBackground: Oxidatively induced DNA damage, an important factor in cancer etiology, is repaired by oxyguanine glycosylase 1 (OGG1). The lower repair capacity genotype (homozygote Cys326Cys) in the OGG1-rs1052133 (Ser326Cys) polymorphism has been associated with cancer risk. However, no information is available in relation to cancer mortality, other causes of death, and modulation by diet. Objective: Our aim was to evaluate the association of the OGG1-rs1052133 with total, cancer, and cardiovascular disease (CVD) mortality and to analyze its modulation by the Mediterranean diet, focusing especially on total vegetable intake as one of the main characteristics of this diet. Design Secondary analysis in the PREDIMED (Prevencion con Dieta Mediterranea) trial is a randomized, controlled trial conducted in Spain from 2003 to 2010. Participants/setting Study participants (n = 7,170) were at high risk for CVD and were aged 55 to 80 years. Intervention Participants were randomly allocated to two groups with a Mediterranean diet intervention or a control diet. Vegetable intake was measured at baseline. Main outcome measures Main outcomes were all-cause, cancer, and CVD mortality after a median follow-up of 4.8 years. Statistical analyses Multivariable-adjusted Cox regression models were fitted. Results: Three hundred eighteen deaths were detected (cancer, n = 127; CVD, n = 81; and other, n = 110). Cys326Cys individuals (prevalence 4.2%) presented higher total mortality rates than Ser326-carriers (P = 0.009). The multivariable-adjusted hazard ratio for Cys326Cys vs Ser326-carrierswas 1.69 (95% CI 1.09 to 2.62; P = 0.018). This association was greater for CVD mortality (P = 0.001). No relationship was detected for cancer mortality in the whole population (hazard ratio 1.07; 95% CI 0.47 to 2.45; P = 0.867), but a significant age interaction (P = 0.048) was observed, as Cys326Cys was associated with cancer mortality in participants <66.5 years (P = 0.029). Recessive effects limited our ability to investigate Cys326Cys x diet interactions for cancer mortality. No statistically significant interactions for total or CVD mortality were found for the Mediterranean diet intervention. However, significant protective interactions for CVD mortality were found for vegetable intake (hazard ratio interaction per standard deviation 0.42; 95% CI 0.18 to 0.98; P = 0.046). Conclusions: In this population, the Cys326Cys-OGG1 genotype was associated with all-cause mortality, mainly CVD instead of cancer mortality. Additional studies are needed to provide further evidence on its dietary modulation.Publication Safety and efficacy of diflunisal in transthyretin cardiac amyloidosis.(Elsevier, 2024-05) Peiró-Aventín, Belén; Cabrera-Romero, Eva; Mora-Ayestarán, Nerea; Domínguez, Fernando; González-López, Esther; Garcia-Pavia, Pablo; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Instituto de Salud Carlos III; Fundación ProCNIC; Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)Publication P53 and BCL-2 family proteins PUMA and NOXA define competitive fitness in pluripotent cell competition.(Public Library of Science (PLOS), 2024-03) Valverde-Lopez, Jose A; Li-Bao, Lin; Sierra, Rocío; Santos, Elisa; Giovinazzo, Giovanna; Díaz-Díaz, Covadonga; Torres, Miguel; Ministerio de Ciencia e Innovación (España); Fundación ProCNIC; Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)Cell Competition is a process by which neighboring cells compare their fitness. As a result, viable but suboptimal cells are selectively eliminated in the presence of fitter cells. In the early mammalian embryo, epiblast pluripotent cells undergo extensive Cell Competition, which prevents suboptimal cells from contributing to the newly forming organism. While competitive ability is regulated by MYC in the epiblast, the mechanisms that contribute to competitive fitness in this context are largely unknown. Here, we report that P53 and its pro-apoptotic targets PUMA and NOXA regulate apoptosis susceptibility and competitive fitness in pluripotent cells. PUMA is widely expressed specifically in pluripotent cells in vitro and in vivo. We found that P53 regulates MYC levels in pluripotent cells, which connects these two Cell Competition pathways, however, MYC and PUMA/NOXA levels are independently regulated by P53. We propose a model that integrates a bifurcated P53 pathway regulating both MYC and PUMA/NOXA levels and determines competitive fitness.Publication Value of the Life's Essential 8 score in cardiovascular health and mortality.(Ediciones Doyma, 2024-05) Augé-Bailac, Ferran; Rossello, XavierPublication Emerging Themes in Genetics of Hypertrophic Cardiomyopathy: Current Status and Clinical Application.(Elsevier, 2024-05) García-Hernández, Soledad; de la Higuera Romero, Luis; Ochoa, Juan Pablo; McKenna, William JHypertrophic cardiomyopathy (HCM), defined clinically by the presence of unexplained left ventricular hypertrophy (LVH), with wall thickness ≥ 1.5 cm, is a phenotype in search of a diagnosis, which is most often a genetically determined, cardiac exclusive, or systemic disorder. Familial evaluation and genetic testing are required for definitive diagnosis. The role of genetic findings in predicting development of disease, outcomes, and increasingly to guide management is evolving with access to larger data sets. The specific mutation and sex of the patient are important determinants that ultimately are likely to guide management. The genetic/familial evaluation is influenced by the accuracy of the clinical diagnosis and the extent/expertise of the genetic laboratory. Genetic testing in a patient with unexplained LVH without systemic manifestations will yield a definite/likely pathogenetic mutation in a sarcomere (30%-50%), regulatory/functional (10%-15%) or metabolic/syndromic (< 5%) gene associated with Mendelian inheritance. The importance of oligo- and polygenic determinants, usually in the absence of Mendelian inheritance, is under investigation with important implications, particularly related to familial evaluation and definition of risk of disease development in relatives of probands. The results of genetic testing are increasingly important in management strategies related to the use of the implantable cardioverter defibrillator for prevention of sudden death, use of myosin inhibitors for refractory symptoms in patients with and without outflow tract obstruction, and-on the immediate horizon-gene therapy. This review will focus on genetic and outcome data in sarcomeric HCM, and minor causative genes with robust evidence of their association will also be considered.Publication Invasive Treatment Strategy in Adults With Frailty and Non-ST-Segment Elevation Myocardial Infarction: A Secondary Analysis of a Randomized Clinical Trial.(American Medical Association, 2024-03-04) Sanchis, Juan; Bueno, Hector; García-Blas, Sergio; Alegre, Oriol; Martí, David; Martínez-Sellés, Manuel; Domínguez-Pérez, Laura; Díez-Villanueva, Pablo; Barrabés, Jose A; Marín, Francisco; Villa, Adolfo; Sanmartín, Marcelo; Llibre, Cinta; Sionís, Alessandro; Carol, Antoni; Fernández-Cisnal, Agustín; Calvo, Elena; Morales, María José; Elízaga, Jaime; Gómez, Iván; Alfonso, Fernando; García Del Blanco, Bruno; Formiga, Francesc; Núñez, Eduardo; Núñez, Julio; Ariza-Solé, Albert; Ministerio de Ciencia e Innovación (España); Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Centro de Investigación Biomédica en Red - CIBERCV (Enfermedades Cardiovasculares)IMPORTANCE The MOSCA-FRAIL randomized clinical trial compared invasive and conservative treatment strategies in patients with frailty with non-ST-segment elevation myocardial infarction (NSTEMI). It showed no differences in the number of days alive and out of the hospital at 1 year. OBJECTIVE To assess the outcomes of the MOSCA-FRAIL trial during extended follow-up. DESIGN, SETTING, AND PARTICIPANTS The MOSCA-FRAIL randomized clinical trial was conducted at 13 hospitals in Spain between July 7, 2017, and January 9, 2021, and included 167 adults (aged ≥70 years) with frailty (Clinical Frailty Scale score ≥4) and NSTEMI. In this preplanned secondary analysis, follow-up was extended to January 31, 2023. Data analysis was performed from April 5 to 29, 2023, using the intention-to-treat principle. INTERVENTIONS Patients were randomized to a routine invasive (coronary angiography and revascularization if feasible [n = 84]) or a conservative (medical treatment with coronary angiography only if recurrent ischemia [n = 83]) strategy. MAIN OUTCOMES AND MEASURES The primary end point was the difference in restricted mean survival time (RMST). Secondary end points included readmissions for any cause, considering recurrent readmissions. RESULTS Among the 167 patients included in the analysis, the mean (SD) age was 86 (5) years; 79 (47.3%) were men and 88 (52.7%) were women. A total of 93 deaths and 367 readmissions accrued. The RMST for all-cause death over the entire follow-up was 3.13 (95% CI, 2.72-3.60) years in the invasive and 3.06 (95% CI, 2.84-3.32) years in the conservative treatment groups. The RMST analysis showed inconclusive differences in survival time (invasive minus conservative difference, 28 [95% CI, -188 to 230] days). Patients under invasive treatment tended to have shorter survival in the first year (-28 [95% CI, -63 to 7] days), which improved after the first year (192 [95% CI, 90-230] days). Kaplan-Meier mortality curves intersected, displaying higher mortality to 1 year in the invasive group that shifted to a late benefit (landmark analysis hazard ratio, 0.58 [95% CI, 0.33-0.99]; P = .045). Early harm was more evident in the subgroup with a Clinical Frailty Scale score greater than 4. No differences were found for the secondary end points. CONCLUSIONS AND RELEVANCE In this extended follow-up of a randomized clinical trial of patients with frailty and NSTEMI, an invasive treatment strategy did not improve outcomes at a median follow-up of 1113 (IQR, 443-1441) days. However, a differential distribution of deaths was observed, with early harm followed by later benefit. The phenomenon of depletion of susceptible patients may be responsible for this behavior. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03208153.Publication Reply to 'Effects of tafamidis on heart failure hospitalization: The tale of the dog that did not bark'.(Wiley, 2024-02) Elliott, Perry; Gundapaneni, Balarama; Garcia-Pavia, Pablo; PfizerPublication Deterministic reprogramming of neutrophils within tumors.(American Association for the Advancement of Science (AAAS), 2024-01-12) Ng, Melissa S F; Kwok, Immanuel; Tan, Leonard; Shi, Changming; Cerezo-Wallis, Daniela; Tan, Yingrou; Leong, Keith; Calvo, Gabriel F; Yang, Katharine; Zhang, Yuning; Jin, Jingsi; Liong, Ka Hang; Wu, Dandan; He, Rui; Liu, Dehua; Teh, Ye Chean; Bleriot, Camille; Caronni, Nicoletta; Liu, Zhaoyuan; Duan, Kaibo; Narang, Vipin; Ballesteros, Iván; Moalli, Federica; Li, Mengwei; Chen, Jinmiao; Liu, Yao; Liu, Lianxin; Qi, Jingjing; Liu, Yingbin; Jiang, Lingxi; Shen, Baiyong; Cheng, Hui; Cheng, Tao; Angeli, Veronique; Sharma, Ankur; Loh, Yuin-Han; Tey, Hong Liang; Chong, Shu Zhen; Iannacone, Matteo; Ostuni, Renato; Hidalgo, Andrés; Ginhoux, Florent; Ng, Lai Guan; Singapore Immunology Network; National Natural Science Foundation of China; Shanghai Science and Technology Commission; National Medical Research Council of Singapore; Ministerio de Ciencia e Innovación (España); Fundación BBVA; Unión Europea. Comisión Europea. European Research Council (ERC); Fundación La Caixa; Fondation LeducqNeutrophils are increasingly recognized as key players in the tumor immune response and are associated with poor clinical outcomes. Despite recent advances characterizing the diversity of neutrophil states in cancer, common trajectories and mechanisms governing the ontogeny and relationship between these neutrophil states remain undefined. Here, we demonstrate that immature and mature neutrophils that enter tumors undergo irreversible epigenetic, transcriptional, and proteomic modifications to converge into a distinct, terminally differentiated dcTRAIL-R1+ state. Reprogrammed dcTRAIL-R1+ neutrophils predominantly localize to a glycolytic and hypoxic niche at the tumor core and exert pro-angiogenic function that favors tumor growth. We found similar trajectories in neutrophils across multiple tumor types and in humans, suggesting that targeting this program may provide a means of enhancing certain cancer immunotherapies.Publication Efficacy and Safety of Aficamten in Symptomatic Nonobstructive Hypertrophic Cardiomyopathy: Results From the REDWOOD-HCM Trial, Cohort 4.(Elsevier, 2024-03-15) Masri, Ahmad; Sherrid, Mark V; Abraham, Theodore P; Choudhury, Lubna; Garcia-Pavia, Pablo; Kramer, Christopher M; Barriales-Villa, Roberto; Owens, Anjali T; Rader, Florian; Nagueh, Sherif F; Olivotto, Iacopo; Saberi, Sara; Tower-Rader, Albree; Wong, Timothy C; Coats, Caroline J; Watkins, Hugh; Fifer, Michael A; Solomon, Scott D; Heitner, Stephen B; Jacoby, Daniel L; Kupfer, Stuart; Malik, Fady I; Meng, Lisa; Sohn, Regina L; Wohltman, Amy; Maron, Martin SBACKGROUND This open-label phase 2 trial evaluated the safety and efficacy of aficamten in patients with nonobstructive hypertrophic cardiomyopathy (nHCM). METHODS Patients with symptomatic nHCM (left ventricular outflow tract obstruction gradient ≤ 30 mmHg, left ventricular ejection fraction [LVEF] ≥ 60%, N-terminal pro-B-type natriuretic peptide [NT-proBNP] > 300 pg/mL) received aficamten 5-15 mg once daily (doses adjusted according to echocardiographic LVEF) for 10 weeks. RESULTS We enrolled 41 patients (mean ± SD age 56 ± 16 years; 59% female). At Week 10, 22 (55%) patients experienced an improvement of ≥ 1 New York Heart Association class; 11 (29%) became asymptomatic. Clinically relevant improvements in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores occurred in 22 (55%) patients. Symptom relief was paralleled by reductions in NT-proBNP levels (56%; P < 0.001) and high-sensitivity cardiac troponin I (22%; P < 0.005). Modest reductions in LVEF (mean ± SD) of -5.4% ± 10 to 64.6% ± 9.1 were observed. Three (8%) patients had asymptomatic reduction in LVEF < 50% (range: 41%-48%), all returning to normal after 2 weeks of washout. One patient with prior history of aborted sudden cardiac death experienced a fatal arrhythmia during the study. CONCLUSIONS Aficamten administration for symptomatic nHCM was generally safe and was associated with improvements in heart failure symptoms and cardiac biomarkers. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04219826.Publication Practical approach for atrial cardiomyopathy characterization in patients with atrial fibrillation.(Ediciones Doyma, 2024-02-29) La Rosa, Giulio; Morillo, Carlos A; Quintanilla, Jorge G; Doltra, Adelina; Mont, Lluis; Rodríguez-Mañero, Moisés; Sarkozy, Andrea; Merino, José Luis; Vivas, David; Datino, Tomás; Calvo, David; Pérez-Castellano, Nicasio; Pérez-Villacastín, Julián; Fauchier, Laurent; Lip, Gregory; Hatem, Stéphane N; Jalife, José; Sanchis, Laura; Marín, Francisco; Filgueiras-Rama, David; Unión Europea. Comisión Europea. H2020; Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación (España); Fundación ProCNIC; Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)Atrial fibrillation (AF) causes progressive structural and electrical changes in the atria that can be summarized within the general concept of atrial remodeling. In parallel, other clinical characteristics and comorbidities may also affect atrial tissue properties and make the atria susceptible to AF initiation and its long-term persistence. Overall, pathological atrial changes lead to atrial cardiomyopathy with important implications for rhythm control. Although there is general agreement on the role of the atrial substrate for successful rhythm control in AF, the current classification oversimplifies clinical management. The classification uses temporal criteria and does not establish a well-defined strategy to characterize the individual-specific degree of atrial cardiomyopathy. Better characterization of atrial cardiomyopathy may improve the decision-making process on the most appropriate therapeutic option. We review current scientific evidence and propose a practical characterization of the atrial substrate based on 3 evaluation steps starting with a clinical evaluation (step 1), then assess outpatient complementary data (step 2), and finally include information from advanced diagnostic tools (step 3). The information from each of the steps or a combination thereof can be used to classify AF patients in 4 stages of atrial cardiomyopathy, which we also use to estimate the success on effective rhythm control.Publication Walking the talk for dementia: A unique immersive, embodied, and multi-experiential initiative.(Wiley, 2024-03) Aguzzoli Peres, Fernando; Haas, Aline Nogueira; Martha, Angga Dwi; Chan, Melissa; Steele, Michelle; Ferretti, Maria Teresa; Ngcobo, Ntokozo N; Ilinca, Stefania; Domínguez-Vivero, Clara; Leroi, Iracema; Sajnani, Nisha; Zimmer, Eduardo R; Kornhuber, Alex; Kalache, Alexandre; Holtzhausen, Berrie; Tristão-Pereira, Catarina; Dupont, Charlèss; Cohen, Dan; de Jong, David; Facal, David; O'Sullivan, Desmond; Mateus, Elaine; Roso, Enzo; Estrop, Evon; Gamba, Giulia; San Martin Elexpe, Gustavo; Ulises Diaz Hernández, Hector; Quaid, Helena; Govia, Ishtar; Barbosa, João; García Del Moral, Joaquina; Miller, Johnny; García García, José Antonio; Quaid, Kevin; Navarro, Laura; García, Laura Zúñiga; Waters, Laureen; Molete, Lebo; Godoy, Maria Eugenia; Sigauke, Maureen; de Ataide Schulte, Max William; Estrop, Peter; San Martin Elexpe Cardoso, Priscilla; Perez, Randall; Patterson, Rianna; Chakrabarti, Ronika; Wong, Ruth; Marsillas, Sara; Lowe, Shontonese; Rego, Taida Sánchez; Farombi, Temitope; Montgomery, Theresa; In 't Veen, Ton; Yanni, Valli; Weidner, Wendy; Ibanez, AgustinCoping with dementia requires an integrated approach encompassing personal, health, research, and community domains. Here we describe "Walking the Talk for Dementia," an immersive initiative aimed at empowering people with dementia, enhancing dementia understanding, and inspiring collaborations. This initiative involved 300 participants from 25 nationalities, including people with dementia, care partners, clinicians, policymakers, researchers, and advocates for a 4-day, 40 km walk through the Camino de Santiago de Compostela, Spain. A 2-day symposium after the journey provided novel transdisciplinary and horizontal structures, deconstructing traditional hierarchies. The innovation of this initiative lies in its ability to merge a physical experience with knowledge exchange for diversifying individuals' understanding of dementia. It showcases the transformative potential of an immersive, embodied, and multi-experiential approach to address the complexities of dementia collaboratively. The initiative offers a scalable model to enhance understanding, decrease stigma, and promote more comprehensive and empathetic dementia care and research.Publication POS0808 MICA/B-DEPENDENT ACTIVATION OF CYTOTOXIC NATURAL KILLER CELLS BY INFLAMMATORY CDC2 CONTRIBUTE TO PRIMARY SJÖGREN´S SYNDROME PATHOLOGY(BMJ Publishing Group, 2023) Sánchez-Cerrillo, I.; Calvet-Mirabent, M.; Triguero-Martinez, A.; Calzada Fraile, D.; Delgado-Arévalo, C.; Valdivia, M.; Ramirez, M.; Vazquez de Luis, E.; Benguría-Filippini, A.; Moreno, R.; Adrados de Llano, M.; De la Fuente, H.; Tsukalov, I.; Roy Vallejo, E.; Ramino, A.; Iborra, S.; Sánchez-Madrid, F.; Dopazo, A.; González-Álvaro, I.; Castañeda, S.; Martin-Gayo, E.Publication The '10 commandments' for the 2023 ESC Guidelines for the management of acute coronary syndromes.(Oxford University Press, 2024-04-07) Byrne, Robert; Coughlan, J J; Rossello, Xavier; Ibáñez, BorjaPublication A mammalian-specific Alex3/Gαq protein complex regulates mitochondrial trafficking, dendritic complexity, and neuronal survival.(American Association for the Advancement of Science (AAAS), 2024-02-06) Izquierdo-Villalba, Ismael; Mirra, Serena; Manso, Yasmina; Parcerisas, Antoni; Rubio, Javier; Del Valle, Jaume; Gil-Bea, Francisco J; Ulloa, Fausto; Herrero-Lorenzo, Marina; Verdaguer, Ester; Benincá, Cristiane; Castro-Torres, Rubén D; Rebollo, Elena; Marfany, Gemma; Auladell, Carme; Navarro, Xavier; Enriquez, Jose Antonio; López de Munain, Adolfo; Soriano, Eduardo; Aragay, Anna M; Ministerio de Ciencia e Innovación (España); Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España); Fundación ProCNICMitochondrial dynamics and trafficking are essential to provide the energy required for neurotransmission and neural activity. We investigated how G protein-coupled receptors (GPCRs) and G proteins control mitochondrial dynamics and trafficking. The activation of Gαq inhibited mitochondrial trafficking in neurons through a mechanism that was independent of the canonical downstream PLCβ pathway. Mitoproteome analysis revealed that Gαq interacted with the Eutherian-specific mitochondrial protein armadillo repeat-containing X-linked protein 3 (Alex3) and the Miro1/Trak2 complex, which acts as an adaptor for motor proteins involved in mitochondrial trafficking along dendrites and axons. By generating a CNS-specific Alex3 knockout mouse line, we demonstrated that Alex3 was required for the effects of Gαq on mitochondrial trafficking and dendritic growth in neurons. Alex3-deficient mice had altered amounts of ER stress response proteins, increased neuronal death, motor neuron loss, and severe motor deficits. These data revealed a mammalian-specific Alex3/Gαq mitochondrial complex, which enables control of mitochondrial trafficking and neuronal death by GPCRs.Publication ICAMs in Immunity, Intercellular Adhesion and Communication.(Multidisciplinary Digital Publishing Institute (MDPI), 2024-02-14) Guerra-Espinosa, Claudia; Jiménez-Fernández, María; Sánchez-Madrid, Francisco; Serrador, Juan M; Ministerio de Ciencia, Innovación y Universidades (España); Fundación La Caixa; Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación (España); Fundación ProCNICInteractions among leukocytes and leukocytes with immune-associated auxiliary cells represent an essential feature of the immune response that requires the involvement of cell adhesion molecules (CAMs). In the immune system, CAMs include a wide range of members pertaining to different structural and functional families involved in cell development, activation, differentiation and migration. Among them, β2 integrins (LFA-1, Mac-1, p150,95 and αDβ2) are predominantly involved in homotypic and heterotypic leukocyte adhesion. β2 integrins bind to intercellular (I)CAMs, actin cytoskeleton-linked receptors belonging to immunoglobulin superfamily (IgSF)-CAMs expressed by leukocytes and vascular endothelial cells, enabling leukocyte activation and transendothelial migration. β2 integrins have long been viewed as the most important ICAMs partners, propagating intracellular signalling from β2 integrin-ICAM adhesion receptor interaction. In this review, we present previous evidence from pioneering studies and more recent findings supporting an important role for ICAMs in signal transduction. We also discuss the contribution of immune ICAMs (ICAM-1, -2, and -3) to reciprocal cell signalling and function in processes in which β2 integrins supposedly take the lead, paying particular attention to T cell activation, differentiation and migration.Publication Impact of vutrisiran on exploratory cardiac parameters in hereditary transthyretin-mediated amyloidosis with polyneuropathy.(Wiley, 2024-02) Garcia-Pavia, Pablo; Grogan, Martha; Kale, Parag; Berk, John L; Maurer, Mathew S; Conceição, Isabel; Di Carli, Marcelo; Solomon, Scott D; Chen, Chongshu; Yureneva, Elena; Vest, John; Gillmore, Julian DAIMS HELIOS-A was a Phase 3, open-label study of vutrisiran, an RNA interference therapeutic, in patients with hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy. This analysis evaluated vutrisiran's impact on exploratory cardiac endpoints in HELIOS-A patients. METHODS AND RESULTS Patients were randomized 3:1 to subcutaneous vutrisiran 25 mg every 3 months or intravenous patisiran 0.3 mg/kg every 3 weeks (reference group) for 18 months. Exploratory cardiac endpoints included change from baseline in N-terminal prohormone of brain-type natriuretic peptide (NT-proBNP) and echocardiographic parameters versus external placebo (APOLLO study). The modified intent-to-treat (mITT) population comprised randomized patients receiving any study drug (n = 122). A cardiac subpopulation with evidence of cardiac amyloid involvement (n = 40) was prespecified. 99mTc scintigraphy exploratory assessments in a planned vutrisiran-treated cohort at select sites were compared with baseline. At Month 18, vutrisiran demonstrated beneficial effects on NT-proBNP versus external placebo in the mITT and cardiac subpopulations (adjusted geometric mean fold change ratio [95% confidence interval] 0.480 [0.383-0.600], p = 9.606 × 10-10 and 0.491 [0.337-0.716], p = 0.0004, respectively). Benefits or trends towards benefit in echocardiographic parameters versus external placebo were observed for both populations. In 99mTc scintigraphy assessments, 32/47 (68.1%) and 31/48 (64.6%) patients exhibited reduced normalized left ventricular total uptake and heart-to-contralateral lung ratio, respectively. Perugini grade was reduced or unchanged versus baseline in 55/57 (96.5%) evaluable patients. No increase in cardiac adverse events was observed with vutrisiran versus external placebo. CONCLUSIONS Vutrisiran demonstrated evidence of potential benefit on cardiac manifestations in patients with ATTRv amyloidosis with polyneuropathy, with an acceptable safety profile.Publication Leukemic cell-secreted interleukin-9 suppresses cytotoxic T cell-mediated killing in chronic lymphocytic leukemia.(Springer, 2024-02-15) Boncompagni, Gioia; Tatangelo, Vanessa; Lopresti, Ludovica; Ulivieri, Cristina; Capitani, Nagaja; Tangredi, Carmela; Finetti, Francesca; Marotta, Giuseppe; Frezzato, Federica; Visentin, Andrea; Ciofini, Sara; Gozzetti, Alessandro; Bocchia, Monica; Calzada-Fraile, Diego; Martin Cofreces, Noa B; Trentin, Livio; Patrussi, Laura; Baldari, Cosima T; Unión Europea. Comisión Europea. H2020The tumor microenvironment (TME) plays a central role in the pathogenesis of chronic lymphocytic leukemia (CLL), contributing to disease progression and chemoresistance. Leukemic cells shape the TME into a pro-survival and immunosuppressive niche through contact-dependent and contact-independent interactions with the cellular components of the TME. Immune synapse (IS) formation is defective in CLL. Here we asked whether soluble factors released by CLL cells contribute to their protection from cytotoxic T cell (CTL)-mediated killing by interfering with this process. We found that healthy CTLs cultured in media conditioned by leukemic cells from CLL patients or Eμ-TCL1 mice upregulate the exhaustion marker PD-1 and become unable to form functional ISs and kill target cells. These defects were more pronounced when media were conditioned by leukemic cells lacking p66Shc, a proapoptotic adapter whose deficiency has been implicated in disease aggressiveness both in CLL and in the Eμ-TCL1 mouse model. Multiplex ELISA assays showed that leukemic cells from Eμ-TCL1 mice secrete abnormally elevated amounts of CCL22, CCL24, IL-9 and IL-10, which are further upregulated in the absence of p66Shc. Among these, IL-9 and IL-10 were also overexpressed in leukemic cells from CLL patients, where they inversely correlated with residual p66Shc. Using neutralizing antibodies or the recombinant cytokines we show that IL-9, but not IL-10, mediates both the enhancement in PD-1 expression and the suppression of effector functions in healthy CTLs. Our results demonstrate that IL-9 secreted by leukemic cells negatively modulates the anti-tumor immune abilities of CTLs, highlighting a new suppressive mechanism and a novel potential therapeutical target in CLL.Publication The inflammatory spectrum of cardiomyopathies.(Frontiers Media, 2024) Musigk, Nicolas; Suwalski, Phillip; Golpour, Ainoosh; Fairweather, DeLisa; Klingel, Karin; Martin, Pilar; Frustaci, Andrea; Cooper, Leslie T; Lüscher, Thomas F; Landmesser, Ulf; Heidecker, Bettina; National Institutes of Health (Estados Unidos); American Heart Association; Ministerio de Ciencia e Innovación (España); Instituto de Salud Carlos IIIInfiltration of the myocardium with various cell types, cytokines and chemokines plays a crucial role in the pathogenesis of cardiomyopathies including inflammatory cardiomyopathies and myocarditis. A more comprehensive understanding of the precise immune mechanisms involved in acute and chronic myocarditis is essential to develop novel therapeutic approaches. This review offers a comprehensive overview of the current knowledge of the immune landscape in cardiomyopathies based on etiology. It identifies gaps in our knowledge about cardiac inflammation and emphasizes the need for new translational approaches to improve our understanding thus enabling development of novel early detection methods and more effective treatments.Publication Association between subclinical atherosclerosis burden and unrecognized myocardial infarction detected by cardiac magnetic resonance in middle-aged low-risk adults.(Oxford University Press, 2024-06-28) Fernández-Friera, Leticia; García-Alvarez, Ana; Oliva, Belen; García-Lunar, Inés; García, Iris; Moreno-Arciniegas, Andrea; Gómez-Talavera, Sandra; Pérez-Herreras, Cristina; Sánchez-González, Javier; de Vega, Vicente Martinez; Rossello, Xavier; Bueno, Héctor; Fernández-Ortiz, Antonio; Ibañez, Borja; Sanz, Javier; Fuster, Valentín; Centro Nacional de Investigaciones Cardiovasculares Carlos III (España); Banco Santander; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Ministerio de Ciencia e Innovación (España); Fundación ProCNIC; Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)AIMS Evidence on the association between subclinical atherosclerosis (SA) and cardiovascular (CV) events in low-risk populations is scant. To study the association between SA burden and an ischaemic scar (IS), identified by cardiac magnetic resonance (CMR), as a surrogate of CV endpoint, in a low-risk population. METHODS AND RESULTS A cohort of 712 asymptomatic middle-aged individuals from the Progression of Early SA (PESA-CNIC-Santander) study (median age 51 years, 84% male, median SCORE2 3.37) were evaluated on enrolment and at 3-year follow-up with 2D/3D vascular ultrasound (VUS) and coronary artery calcification scoring (CACS). A cardiac magnetic study (CMR) was subsequently performed and IS defined as the presence of subendocardial or transmural late gadolinium enhancement (LGE). On CMR, 132 (19.1%) participants had positive LGE, and IS was identified in 20 (2.9%) participants. Individuals with IS had significantly higher SCORE2 at baseline and higher CACS and peripheral SA burden (number of plaques by 2DVUS and plaque volume by 3DVUS) at both SA evaluations. High CACS and peripheral SA (number of plaques) burden were independently associated with the presence of IS, after adjusting for SCORE2 [OR for 3rd tertile, 8.31; 95% confidence interval (CI) 2.85-24.2; P < 0.001; and 2.77; 95% CI, 1.02-7.51; P = 0.045, respectively] and provided significant incremental diagnostic value over SCORE2. CONCLUSION In a low-risk middle-aged population, SA burden (CAC and peripheral plaques) was independently associated with a higher prevalence of IS identified by CMR. These findings reinforce the value of SA evaluation to early implement preventive measures. CLINICAL TRIAL REGISTRATION Progression of Early Subclinical Atherosclerosis (PESA) Study Identifier: NCT01410318.Publication Spatial enhancer activation influences inhibitory neuron identity during mouse embryonic development.(Nature Publishing Group, 2024-05) Dvoretskova, Elena; Ho, May C; Kittke, Volker; Neuhaus, Florian; Vitali, Ilaria; Lam, Daniel D; Delgado, Irene; Feng, Chao; Torres, Miguel; Winkelmann, Juliane; Mayer, Christian; Unión Europea. Comisión Europea. European Research Council (ERC); Unión Europea. Comisión Europea. H2020The mammalian telencephalon contains distinct GABAergic projection neuron and interneuron types, originating in the germinal zone of the embryonic basal ganglia. How genetic information in the germinal zone determines cell types is unclear. Here we use a combination of in vivo CRISPR perturbation, lineage tracing and ChIP-sequencing analyses and show that the transcription factor MEIS2 favors the development of projection neurons by binding enhancer regions in projection-neuron-specific genes during mouse embryonic development. MEIS2 requires the presence of the homeodomain transcription factor DLX5 to direct its functional activity toward the appropriate binding sites. In interneuron precursors, the transcription factor LHX6 represses the MEIS2-DLX5-dependent activation of projection-neuron-specific enhancers. Mutations of Meis2 result in decreased activation of regulatory enhancers, affecting GABAergic differentiation. We propose a differential binding model where the binding of transcription factors at cis-regulatory elements determines differential gene expression programs regulating cell fate specification in the mouse ganglionic eminence.