Author: "Javier A, Menendez" - Searchworks@Jio Institute Digital Library Search Results

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1. Fatty acid synthase (FASN) is a tumor-cell-intrinsic metabolic checkpoint restricting T-cell immunity

Author: Elisabet Cuyàs, Stefano Pedarra, Sara Verdura, Miguel Angel Pardo, Roderic Espin Garcia, Eila Serrano-Hervás, Àngela Llop-Hernández, Eduard Teixidor, Joaquim Bosch-Barrera, Eugeni López-Bonet, Begoña Martin-Castillo, Ruth Lupu, Miguel Angel Pujana, Josep Sardanyès, Tomás Alarcón, and Javier A. Menendez
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Cytology, QH573-671
Abstract: Abstract Fatty acid synthase (FASN)-catalyzed endogenous lipogenesis is a hallmark of cancer metabolism. However, whether FASN is an intrinsic mechanism of tumor cell defense against T cell immunity remains unexplored. To test this hypothesis, here we combined bioinformatic analysis of the FASN-related immune cell landscape, real-time assessment of cell-based immunotherapy efficacy in CRISPR/Cas9-based FASN gene knockout (FASN KO) cell models, and mathematical and mechanistic evaluation of FASN-driven immunoresistance. FASN expression negatively correlates with infiltrating immune cells associated with cancer suppression, cytolytic activity signatures, and HLA-I expression. Cancer cells engineered to carry a loss-of-function mutation in FASN exhibit an enhanced cytolytic response and an accelerated extinction kinetics upon interaction with cytokine-activated T cells. Depletion of FASN results in reduced carrying capacity, accompanied by the suppression of mitochondrial OXPHOS and strong downregulation of electron transport chain complexes. Targeted FASN depletion primes cancer cells for mitochondrial apoptosis as it synergizes with BCL-2/BCL-XL-targeting BH3 mimetics to render cancer cells more susceptible to T-cell-mediated killing. FASN depletion prevents adaptive induction of PD-L1 in response to interferon-gamma and reduces constitutive overexpression of PD-L1 by abolishing PD-L1 post-translational palmitoylation. FASN is a novel tumor cell-intrinsic metabolic checkpoint that restricts T cell immunity and may be exploited to improve the efficacy of T cell-based immunotherapy.
Published: 2024
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2. Fatty acid synthase (FASN) signalome: A molecular guide for precision oncology

Author: Javier A. Menendez, Elisabet Cuyàs, Jose Antonio Encinar, Travis Vander Steen, Sara Verdura, Àngela Llop‐Hernández, Júlia López, Eila Serrano‐Hervás, Sílvia Osuna, Begoña Martin‐Castillo, and Ruth Lupu
Subjects: cell fate, ferroptosis, immunotherapy, metastasis, mitochondrial priming, molecular glues, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: The initial excitement generated more than two decades ago by the discovery of drugs targeting fatty acid synthase (FASN)‐catalyzed de novo lipogenesis for cancer therapy was short‐lived. However, the advent of the first clinical‐grade FASN inhibitor (TVB‐2640; denifanstat), which is currently being studied in various phase II trials, and the exciting advances in understanding the FASN signalome are fueling a renewed interest in FASN‐targeted strategies for the treatment and prevention of cancer. Here, we provide a detailed overview of how FASN can drive phenotypic plasticity and cell fate decisions, mitochondrial regulation of cell death, immune escape and organ‐specific metastatic potential. We then present a variety of FASN‐targeted therapeutic approaches that address the major challenges facing FASN therapy. These include limitations of current FASN inhibitors and the lack of precision tools to maximize the therapeutic potential of FASN inhibitors in the clinic. Rethinking the role of FASN as a signal transducer in cancer pathogenesis may provide molecularly driven strategies to optimize FASN as a long‐awaited target for cancer therapeutics.
Published: 2024
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3. Spatio-Temporal Anomaly Detection with Graph Networks for Data Quality Monitoring of the Hadron Calorimeter

Author: Mulugeta Weldezgina Asres, Christian Walter Omlin, Long Wang, David Yu, Pavel Parygin, Jay Dittmann, Georgia Karapostoli, Markus Seidel, Rosamaria Venditti, Luka Lambrecht, Emanuele Usai, Muhammad Ahmad, Javier Fernandez Menendez, Kaori Maeshima, and the CMS-HCAL Collaboration
Subjects: anomaly detection, monitoring, spatio-temporal, deep learning, graph networks, particle sensors, Chemical technology, TP1-1185
Abstract: The Compact Muon Solenoid (CMS) experiment is a general-purpose detector for high-energy collision at the Large Hadron Collider (LHC) at CERN. It employs an online data quality monitoring (DQM) system to promptly spot and diagnose particle data acquisition problems to avoid data quality loss. In this study, we present a semi-supervised spatio-temporal anomaly detection (AD) monitoring system for the physics particle reading channels of the Hadron Calorimeter (HCAL) of the CMS using three-dimensional digi-occupancy map data of the DQM. We propose the GraphSTAD system, which employs convolutional and graph neural networks to learn local spatial characteristics induced by particles traversing the detector and the global behavior owing to shared backend circuit connections and housing boxes of the channels, respectively. Recurrent neural networks capture the temporal evolution of the extracted spatial features. We validate the accuracy of the proposed AD system in capturing diverse channel fault types using the LHC collision data sets. The GraphSTAD system achieves production-level accuracy and is being integrated into the CMS core production system for real-time monitoring of the HCAL. We provide a quantitative performance comparison with alternative benchmark models to demonstrate the promising leverage of the presented system.
Published: 2023
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4. Fatty acid synthase (FASN) regulates the mitochondrial priming of cancer cells

Author: Barbara Schroeder, Travis Vander Steen, Ingrid Espinoza, Chandra M. Kurapaty Venkatapoorna, Zeng Hu, Fernando Martín Silva, Kevin Regan, Elisabet Cuyàs, X. Wei Meng, Sara Verdura, Aina Arbusà, Paula A. Schneider, Karen S. Flatten, George Kemble, Joan Montero, Scott H. Kaufmann, Javier A. Menendez, and Ruth Lupu
Subjects: Cytology, QH573-671
Abstract: Abstract Inhibitors of the lipogenic enzyme fatty acid synthase (FASN) have attracted much attention in the last decade as potential targeted cancer therapies. However, little is known about the molecular determinants of cancer cell sensitivity to FASN inhibitors (FASNis), which is a major roadblock to their therapeutic application. Here, we find that pharmacological starvation of endogenously produced FAs is a previously unrecognized metabolic stress that heightens mitochondrial apoptotic priming and favors cell death induction by BH3 mimetic inhibitors. Evaluation of the death decision circuits controlled by the BCL-2 family of proteins revealed that FASN inhibition is accompanied by the upregulation of the pro-death BH3-only proteins BIM, PUMA, and NOXA. Cell death triggered by FASN inhibition, which causally involves a palmitate/NADPH-related redox imbalance, is markedly diminished by concurrent loss of BIM or PUMA, suggesting that FASN activity controls cancer cell survival by fine-tuning the BH3 only proteins-dependent mitochondrial threshold for apoptosis. FASN inhibition results in a heightened mitochondrial apoptosis priming, shifting cells toward a primed-for-death state “addicted” to the anti-apoptotic protein BCL-2. Accordingly, co-administration of a FASNi synergistically augments the apoptosis-inducing activity of the dual BCL-XL/BCL-2 inhibitor ABT-263 (navitoclax) and the BCL-2 specific BH3-mimetic ABT-199 (venetoclax). FASN inhibition, however, fails to sensitize breast cancer cells to MCL-1- and BCL-XL-selective inhibitors such as S63845 and A1331852. A human breast cancer xenograft model evidenced that oral administration of the only clinically available FASNi drastically sensitizes FASN-addicted breast tumors to ineffective single-agents navitoclax and venetoclax in vivo. In summary, a novel FASN-driven facet of the mitochondrial priming mechanistically links the redox-buffering mechanism of FASN activity to the intrinsic apoptotic threshold in breast cancer cells. Combining next-generation FASNis with BCL-2-specific BH3 mimetics that directly activate the apoptotic machinery might generate more potent and longer-lasting antitumor responses in a clinical setting.
Published: 2021
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5. The oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer

Author: Emily Golden, Rabab Rashwan, Eleanor A. Woodward, Agustin Sgro, Edina Wang, Anabel Sorolla, Charlene Waryah, Wan Jun Tie, Elisabet Cuyàs, Magdalena Ratajska, Iwona Kardaś, Piotr Kozlowski, Elizabeth K. M. Johnstone, Heng B. See, Ciara Duffy, Jeremy Parry, Kim A. Lagerborg, Piotr Czapiewski, Javier A. Menendez, Adam Gorczyński, Bartosz Wasag, Kevin D. G. Pfleger, Christina Curtis, Bum-Kyu Lee, Jonghwan Kim, Joseph Cursons, Nathan J. Pavlos, Wojciech Biernat, Mohit Jain, Andrew J. Woo, Andrew Redfern, and Pilar Blancafort
Subjects: Science
Abstract: Adipogenesis associated Mth938 Domain Containing gene (AAMDC) is frequently amplified in the IntClus2 subgroup of ER + breast cancer. Here, the authors show that AAMDC drives tumourigenesis through activating PI3K-AKT-mTOR pathway for metabolic reprogramming.
Published: 2021
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6. Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis

Author: Carmen Herranz, Francesca Mateo, Alexandra Baiges, Gorka Ruiz de Garibay, Alexandra Junza, Simon R Johnson, Suzanne Miller, Nadia García, Jordi Capellades, Antonio Gómez, August Vidal, Luis Palomero, Roderic Espín, Ana I Extremera, Eline Blommaert, Eva Revilla‐López, Berta Saez, Susana Gómez‐Ollés, Julio Ancochea, Claudia Valenzuela, Tamara Alonso, Piedad Ussetti, Rosalía Laporta, Antoni Xaubet, José A Rodríguez‐Portal, Ana Montes‐Worboys, Carlos Machahua, Jaume Bordas, Javier A Menendez, Josep M Cruzado, Roser Guiteras, Christophe Bontoux, Concettina La Motta, Aleix Noguera‐Castells, Mario Mancino, Enrique Lastra, Raúl Rigo‐Bonnin, Jose C Perales, Francesc Viñals, Alvaro Lahiguera, Xiaohu Zhang, Daniel Cuadras, Coline H M vanMoorsel, Joanne J van derVis, Marian J R Quanjel, Harilaos Filippakis, Razq Hakem, Chiara Gorrini, Marc Ferrer, Aslihan Ugun‐Klusek, Ellen Billett, Elżbieta Radzikowska, Álvaro Casanova, María Molina‐Molina, Antonio Roman, Oscar Yanes, and Miquel A Pujana
Subjects: biomarker, histamine, lymphangioleiomyomatosis, mTOR, therapy, Medicine (General), R5-920, Genetics, QH426-470
Abstract: Abstract Inhibition of mTOR is the standard of care for lymphangioleiomyomatosis (LAM). However, this therapy has variable tolerability and some patients show progressive decline of lung function despite treatment. LAM diagnosis and monitoring can also be challenging due to the heterogeneity of symptoms and insufficiency of non‐invasive tests. Here, we propose monoamine‐derived biomarkers that provide preclinical evidence for novel therapeutic approaches. The major histamine‐derived metabolite methylimidazoleacetic acid (MIAA) is relatively more abundant in LAM plasma, and MIAA values are independent of VEGF‐D. Higher levels of histamine are associated with poorer lung function and greater disease burden. Molecular and cellular analyses, and metabolic profiling confirmed active histamine signaling and metabolism. LAM tumorigenesis is reduced using approved drugs targeting monoamine oxidases A/B (clorgyline and rasagiline) or histamine H1 receptor (loratadine), and loratadine synergizes with rapamycin. Depletion of Maoa or Hrh1 expression, and administration of an L‐histidine analog, or a low L‐histidine diet, also reduce LAM tumorigenesis. These findings extend our knowledge of LAM biology and suggest possible ways of improving disease management.
Published: 2021
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7. Silibinin Suppresses the Hyperlipidemic Effects of the ALK-Tyrosine Kinase Inhibitor Lorlatinib in Hepatic Cells

Author: Sara Verdura, José Antonio Encinar, Salvador Fernández-Arroyo, Jorge Joven, Elisabet Cuyàs, Joaquim Bosch-Barrera, and Javier A. Menendez
Subjects: lorlatinib, hypertriglyceridemia, hypercholesteremia, silibinin, lipidomics, CYP3A4, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: The third-generation anaplastic lymphoma tyrosine kinase inhibitor (ALK-TKI) lorlatinib has a unique side effect profile that includes hypercholesteremia and hypertriglyceridemia in >80% of lung cancer patients. Here, we tested the hypothesis that lorlatinib might directly promote the accumulation of cholesterol and/or triglycerides in human hepatic cells. We investigated the capacity of the hepatoprotectant silibinin to modify the lipid-modifying activity of lorlatinib. To predict clinically relevant drug–drug interactions if silibinin were used to clinically manage lorlatinib-induced hyperlipidemic effects in hepatic cells, we also explored the capacity of silibinin to interact with and block CYP3A4 activity using in silico computational descriptions and in vitro biochemical assays. A semi-targeted ultrahigh pressure liquid chromatography accurate mass quadrupole time-of-flight mass spectrometry with electrospray ionization (UHPLC-ESI-QTOF-MS/MS)-based lipidomic approach revealed that short-term treatment of hepatic cells with lorlatinib promotes the accumulation of numerous molecular species of cholesteryl esters and triglycerides. Silibinin treatment significantly protected the steady-state lipidome of hepatocytes against the hyperlipidemic actions of lorlatinib. Lipid staining confirmed the ability of lorlatinib to promote neutral lipid overload in hepatocytes upon long-term exposure, which was prevented by co-treatment with silibinin. Computational analyses and cell-free biochemical assays predicted a weak to moderate inhibitory activity of clinically relevant concentrations of silibinin against CYP3A4 when compared with recommended (rosuvastatin) and non-recommended (simvastatin) statins for lorlatinib-associated dyslipidemia. The elevated plasma cholesterol and triglyceride levels in lorlatinib-treated lung cancer patients might involve primary alterations in the hepatic accumulation of lipid intermediates. Silibinin could be clinically explored to reduce the undesirable hyperlipidemic activity of lorlatinib in lung cancer patients.
Published: 2022
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8. Nutritional Niches of Cancer Therapy-Induced Senescent Cells

Author: Àngela Llop-Hernández, Sara Verdura, Elisabet Cuyàs, and Javier A. Menendez
Subjects: senescence, metabolism, glutamine, nutrition, cancer, miR146a, Nutrition. Foods and food supply, TX341-641
Abstract: Therapy-induced senescence (TIS) is a state of stable proliferative arrest of both normal and neoplastic cells that is triggered by exposure to anticancer treatments. TIS cells acquire a senescence-associated secretory phenotype (SASP), which is pro-inflammatory and actively promotes tumor relapse and adverse side-effects in patients. Here, we hypothesized that TIS cells adapt their scavenging and catabolic ability to overcome the nutritional constraints in their microenvironmental niches. We used a panel of mechanistically-diverse TIS triggers (i.e., bleomycin, doxorubicin, alisertib, and palbociclib) and Biolog Phenotype MicroArrays to identify (among 190 different carbon and nitrogen sources) candidate metabolites that support the survival of TIS cells in limiting nutrient conditions. We provide evidence of distinguishable TIS-associated nutrient consumption profiles involving a core set of shared (e.g., glutamine) and unique (e.g., glucose-1-phosphate, inosine, and uridine) nutritional sources after diverse senescence-inducing interventions. We also observed a trend for an inverse correlation between the intensity of the pro-inflammatory SASP provoked by different TIS agents and diversity of compensatory nutritional niches utilizable by senescent cells. These findings support the detailed exploration of the nutritional niche as a new metabolic dimension to understand and target TIS in cancer.
Published: 2022
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9. Bivalent chromatin as a therapeutic target in cancer: An in silico predictive approach for combining epigenetic drugs.

Author: Tomás Alarcón, Josep Sardanyés, Antoni Guillamon, and Javier A Menendez
Subjects: Biology (General), QH301-705.5
Abstract: Tumour cell heterogeneity is a major barrier for efficient design of targeted anti-cancer therapies. A diverse distribution of phenotypically distinct tumour-cell subpopulations prior to drug treatment predisposes to non-uniform responses, leading to the elimination of sensitive cancer cells whilst leaving resistant subpopulations unharmed. Few strategies have been proposed for quantifying the variability associated to individual cancer-cell heterogeneity and minimizing its undesirable impact on clinical outcomes. Here, we report a computational approach that allows the rational design of combinatorial therapies involving epigenetic drugs against chromatin modifiers. We have formulated a stochastic model of a bivalent transcription factor that allows us to characterise three different qualitative behaviours, namely: bistable, high- and low-gene expression. Comparison between analytical results and experimental data determined that the so-called bistable and high-gene expression behaviours can be identified with undifferentiated and differentiated cell types, respectively. Since undifferentiated cells with an aberrant self-renewing potential might exhibit a cancer/metastasis-initiating phenotype, we analysed the efficiency of combining epigenetic drugs against the background of heterogeneity within the bistable sub-ensemble. Whereas single-targeted approaches mostly failed to circumvent the therapeutic problems represented by tumour heterogeneity, combinatorial strategies fared much better. Specifically, the more successful combinations were predicted to involve modulators of the histone H3K4 and H3K27 demethylases KDM5 and KDM6A/UTX. Those strategies involving the H3K4 and H3K27 methyltransferases MLL2 and EZH2, however, were predicted to be less effective. Our theoretical framework provides a coherent basis for the development of an in silico platform capable of identifying the epigenetic drugs combinations best-suited to therapeutically manage non-uniform responses of heterogenous cancer cell populations.
Published: 2021
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10. Stratification of cancer and diabetes based on circulating levels of formate and glucose

Author: Matthias Pietzke, Salvador Fernandez Arroyo, David Sumpton, Gillian M. Mackay, Begoña Martin-Castillo, Jordi Camps, Jorge Joven, Javier A. Menendez, Alexei Vazquez, and On behalf of the METTEN study group
Subjects: Cancer, Obesity, Biomarker, Serum metabolomics, Formate, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Serum and urine metabolites have been investigated for their use as cancer biomarkers. The specificity of candidate metabolites can be limited by the impact of other disorders on metabolite levels. In particular, the increasing incidence of obesity could become a significant confounding factor. Methods Here we developed a multinomial classifier for the stratification of cancer, obesity and healthy phenotypes based on circulating glucose and formate levels. We quantified the classifier performance from the retrospective analysis of samples from breast cancer, lung cancer, obese individuals and healthy controls. Results We discovered that circulating formate levels are significantly lower in breast and lung cancer patients than in healthy controls. However, the performance of a cancer classifier based on formate levels alone is limited because obese patients also have low serum formate levels. By introducing a multinomial classifier based on circulating glucose and formate levels, we were able to improve the classifier performance, reaching a true positive rate of 79% with a false positive rate of 8%. Conclusions Circulating formate is reduced in HER2+ breast cancer, non-small cell lung cancer and highly obese patients relative to healthy controls. Further studies are required to determine the relevance of these observations in other cancer types and diseases.
Published: 2019
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11. Metformin: Targeting the Metabolo-Epigenetic Link in Cancer Biology

Author: Elisabet Cuyàs, Sara Verdura, Begoña Martin-Castillo, and Javier A. Menendez
Subjects: metformin, metabolism, epigenetics, chromatin, cancer, diet, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Metabolism can directly drive or indirectly enable an aberrant chromatin state of cancer cells. The physiological and molecular principles of the metabolic link to epigenetics provide a basis for pharmacological modulation with the anti-diabetic biguanide metformin. Here, we briefly review how metabolite-derived chromatin modifications and the metabolo-epigenetic machinery itself are both amenable to modification by metformin in a local and a systemic manner. First, we consider the capacity of metformin to target global metabolic pathways or specific metabolic enzymes producing chromatin-modifying metabolites. Second, we examine its ability to directly or indirectly fine-tune the activation status of chromatin-modifying enzymes. Third, we envision how the interaction between metformin, diet and gut microbiota might systemically regulate the metabolic inputs to chromatin. Experimental and clinical validation of metformin’s capacity to change the functional outcomes of the metabolo-epigenetic link could offer a proof-of-concept to therapeutically test the metabolic adjustability of the epigenomic landscape of cancer.
Published: 2021
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12. Metformin and Breast Cancer: Where Are We Now?

Author: Mónica Cejuela, Begoña Martin-Castillo, Javier A. Menendez, and Sonia Pernas
Subjects: metformin, breast cancer, diabetes, insulin, clinical trials, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Breast cancer is the most prevalent cancer and the leading cause of cancer-related death among women worldwide. Type 2 diabetes–associated metabolic traits such as hyperglycemia, hyperinsulinemia, inflammation, oxidative stress, and obesity are well-known risk factors for breast cancer. The insulin sensitizer metformin, one of the most prescribed oral antidiabetic drugs, has been suggested to function as an antitumoral agent, based on epidemiological and retrospective clinical data as well as preclinical studies showing an antiproliferative effect in cultured breast cancer cells and animal models. These benefits provided a strong rationale to study the effects of metformin in routine clinical care of breast cancer patients. However, the initial enthusiasm was tempered after disappointing results in randomized controlled trials, particularly in the metastatic setting. Here, we revisit the current state of the art of metformin mechanisms of action, critically review past and current metformin-based clinical trials, and briefly discuss future perspectives on how to incorporate metformin into the oncologist’s armamentarium for the prevention and treatment of breast cancer.
Published: 2022
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13. Síndrome de quilomicronemia familiar: primer caso reportado en Ecuador

Author: Karla Johana Garay García, Ricardo Javier Chong Menendez, Juan Patricio Nogueira, and Jefferson Santiago Piedra Andrade
Subjects: Pharmacology (medical), Cardiology and Cardiovascular Medicine
Published: 2022

14. Clinical Management of COVID-19 in Cancer Patients with the STAT3 Inhibitor Silibinin

Author: Joaquim Bosch-Barrera, Ariadna Roqué, Eduard Teixidor, Maria Carmen Carmona-Garcia, Aina Arbusà, Joan Brunet, Begoña Martin-Castillo, Elisabet Cuyàs, Sara Verdura, and Javier A. Menendez
Subjects: SARS-CoV-2, COVID-19, STAT3, silibinin, Legalon, COVID-GRAM score, Medicine, Pharmacy and materia medica, RS1-441
Abstract: COVID-19 pathophysiology is caused by a cascade of respiratory and multiorgan failures arising, at least in part, from the SARS-CoV-2-driven dysregulation of the master transcriptional factor STAT3. Pharmacological correction of STAT3 over-stimulation, which is at the root of acute respiratory distress syndrome (ARDS) and coagulopathy/thrombosis events, should be considered for treatment of severe COVID-19. In this perspective, we first review the current body of knowledge on the role of STAT3 in the pathogenesis of severe COVID-19. We then exemplify the potential clinical value of treating COVID-19 disease with STAT3 inhibitors by presenting the outcomes of two hospitalized patients with active cancer and COVID-19 receiving oral Legalon®—a nutraceutical containing the naturally occurring STAT3 inhibitor silibinin. Both patients, which were recruited to the clinical trial SIL-COVID19 (EudraCT number: 2020-001794-77) had SARS-CoV-2 bilateral interstitial pneumonia and a high COVID-GRAM score, and showed systemic proinflammatory responses in terms of lymphocytopenia and hypoalbuminemia. Both patients were predicted to be at high risk of critical COVID-19 illness in terms of intensive care unit admission, invasive ventilation, or death. In addition to physician’s choice of best available therapy or supportive care, patients received 1050 mg/day Legalon® for 10 days without side-effects. Silibinin-treated cancer/COVID-19+ patients required only minimal oxygen support (2–4 L/min) during the episode, exhibited a sharp decline of the STAT3-regulated C-reactive protein, and demonstrated complete resolution of the pulmonary lesions. These findings might inspire future research to advance our knowledge and improve silibinin-based clinical interventions aimed to target STAT3-driven COVID-19 pathophysiology.
Published: 2021
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15. Lung Cancer Management with Silibinin: A Historical and Translational Perspective

Author: Sara Verdura, Elisabet Cuyàs, Verónica Ruiz-Torres, Vicente Micol, Jorge Joven, Joaquim Bosch-Barrera, and Javier A. Menendez
Subjects: silibinin, silymarin, non-small cell lung cancer, EMT, metastasis, STAT3, Medicine, Pharmacy and materia medica, RS1-441
Abstract: The flavonolignan silibinin, the major bioactive component of the silymarin extract of Silybum marianum (milk thistle) seeds, is gaining traction as a novel anti-cancer therapeutic. Here, we review the historical developments that have laid the groundwork for the evaluation of silibinin as a chemopreventive and therapeutic agent in human lung cancer, including translational insights into its mechanism of action to control the aggressive behavior of lung carcinoma subtypes prone to metastasis. First, we summarize the evidence from chemically induced primary lung tumors supporting a role for silibinin in lung cancer prevention. Second, we reassess the preclinical and clinical evidence on the effectiveness of silibinin against drug resistance and brain metastasis traits of lung carcinomas. Third, we revisit the transcription factor STAT3 as a central tumor-cell intrinsic and microenvironmental target of silibinin in primary lung tumors and brain metastasis. Finally, by unraveling the selective vulnerability of silibinin-treated tumor cells to drugs using CRISPR-based chemosensitivity screenings (e.g., the hexosamine biosynthesis pathway inhibitor azaserine), we illustrate how the therapeutic use of silibinin against targetable weaknesses might be capitalized in specific lung cancer subtypes (e.g., KRAS/STK11 co-mutant tumors). Forthcoming studies should take up the challenge of developing silibinin and/or next-generation silibinin derivatives as novel lung cancer-preventive and therapeutic biomolecules.
Published: 2021
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16. Fatty acid synthase: a druggable driver of breast cancer brain metastasis

Author: Javier A, Menendez and Ruth, Lupu
Subjects: Pharmacology, Brain Neoplasms, Lipogenesis, Clinical Biochemistry, Drug Discovery, Tumor Microenvironment, Humans, Molecular Medicine, Breast Neoplasms, Female, Fatty Acid Synthases
Abstract: Brain metastasis (BrM) is a key contributor to morbidity and mortality in breast cancer patients, especially among high-risk epidermal growth factor receptor 2-positive (HER2+) and triple-negative/basal-like molecular subtypes. Optimal management of BrM is focused on characterizing a 'BrM dependency map' to prioritize targetable therapeutic vulnerabilities.We review recent studies addressing the targeting of BrM in the lipid-deprived brain environment, which selects for brain-tropic breast cancer cells capable of cell-autonomously generating fatty acids by upregulatingTargeting FASN represents a new therapeutic opportunity for patients with breast cancer and BrM. Delivery of brain-permeable FASN inhibitors and identifying strategies to target metabolic plasticity that might compensate for impaired brain FASN activity are two potential roadblocks that may hinder FASN-centered strategies against BrM.
Published: 2022

17. Metformin as an archetype immuno-metabolic adjuvant for cancer immunotherapy

Author: Sara Verdura, Elisabet Cuyàs, Begoña Martin-Castillo, and Javier A. Menendez
Subjects: metformin, immunotherapy, t-cells, immune checkpoints, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: The development of a single immuno-metabolic adjuvant capable of modulating, in the appropriate direction and intensity, the complex antagonistic and symbiotic interplays between tumor cells, immune cells, and the gut microbiota may appear pharmacologically implausible. Metformin might help solve this conundrum and beneficially impact the state of cancer-immune system interactions.
Published: 2019
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18. A multiscale model of epigenetic heterogeneity-driven cell fate decision-making.

Author: Núria Folguera-Blasco, Rubén Pérez-Carrasco, Elisabet Cuyàs, Javier A Menendez, and Tomás Alarcón
Subjects: Biology (General), QH301-705.5
Abstract: The inherent capacity of somatic cells to switch their phenotypic status in response to damage stimuli in vivo might have a pivotal role in ageing and cancer. However, how the entry-exit mechanisms of phenotype reprogramming are established remains poorly understood. In an attempt to elucidate such mechanisms, we herein introduce a stochastic model of combined epigenetic regulation (ER)-gene regulatory network (GRN) to study the plastic phenotypic behaviours driven by ER heterogeneity. To deal with such complex system, we additionally formulate a multiscale asymptotic method for stochastic model reduction, from which we derive an efficient hybrid simulation scheme. Our analysis of the coupled system reveals a regime of tristability in which pluripotent stem-like and differentiated steady-states coexist with a third indecisive state, with ER driving transitions between these states. Crucially, ER heterogeneity of differentiation genes is for the most part responsible for conferring abnormal robustness to pluripotent stem-like states. We formulate epigenetic heterogeneity-based strategies capable of unlocking and facilitating the transit from differentiation-refractory (stem-like) to differentiation-primed epistates. The application of the hybrid numerical method validates the likelihood of such switching involving solely kinetic changes in epigenetic factors. Our results suggest that epigenetic heterogeneity regulates the mechanisms and kinetics of phenotypic robustness of cell fate reprogramming. The occurrence of tunable switches capable of modifying the nature of cell fate reprogramming might pave the way for new therapeutic strategies to regulate reparative reprogramming in ageing and cancer.
Published: 2019
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19. The C Allele of ATM rs11212617 Associates With Higher Pathological Complete Remission Rate in Breast Cancer Patients Treated With Neoadjuvant Metformin

Author: Elisabet Cuyàs, Maria Buxó, Maria José Ferri Iglesias, Sara Verdura, Sonia Pernas, Joan Dorca, Isabel Álvarez, Susana Martínez, Jose Manuel Pérez-Garcia, Norberto Batista-López, César A. Rodríguez-Sánchez, Kepa Amillano, Severina Domínguez, Maria Luque, Idoia Morilla, Agostina Stradella, Gemma Viñas, Javier Cortés, Jorge Joven, Joan Brunet, Eugeni López-Bonet, Margarita Garcia, Samiha Saidani, Xavier Queralt Moles, Begoña Martin-Castillo, and Javier A. Menendez
Subjects: metformin, breast cancer, neoadjuvancy, HER2, ATM, rs11212617, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Background: The minor allele (C) of the single-nucleotide polymorphism (SNP) rs11212617, located near the ataxia telangiectasia mutated (ATM) gene, has been associated with an increased likelihood of treatment success with metformin in type 2 diabetes. We herein investigated whether the same SNP would predict clinical response to neoadjuvant metformin in women with early breast cancer (BC).Methods: DNA was collected from 79 patients included in the intention-to-treat population of the METTEN study, a phase 2 clinical trial of HER2-positive BC patients randomized to receive either metformin combined with anthracycline/taxane-based chemotherapy and trastuzumab or equivalent regimen without metformin, before surgery. SNP rs11212617 genotyping was assessed using allelic discrimination by quantitative polymerase chain reaction.Results: Logistic regression analyses revealed a significant relationship between the rs11212617 genotype and the ability of treatment arms to achieve a pathological complete response (pCR) in patients (odds ratio [OR]genotype×arm = 10.33, 95% confidence interval [CI]: 1.29–82.89, p = 0.028). In the metformin-containing arm, patients bearing the rs11212617 C allele had a significantly higher probability of pCR (ORA/C,C/C = 7.94, 95%CI: 1.60–39.42, p = 0.011). Conversely, no association was found between rs11212617 and clinical response in the reference arm (ORA/C,C/C = 0.77, 95%CI: 0.20–2.92, p = 0.700). After controlling for tumor size and hormone receptor status, the rs11212617 C allele remained a significant predictor of pCR solely in the metformin-containing arm.Conclusions: If reproducible, the rs11212617 C allele might warrant consideration as a predictive clinical biomarker to inform the personalized use of metformin in BC patients.Trial Registration: EU Clinical Trials Register, EudraCT number 2011-000490-30. Registered 28 February 2011, https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-000490-30/ES.
Published: 2019
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20. Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation

Author: Elisabet Cuyàs, Sara Verdura, Laura Llorach-Parés, Salvador Fernández-Arroyo, Jorge Joven, Begoña Martin-Castillo, Joaquim Bosch-Barrera, Joan Brunet, Alfons Nonell-Canals, Melchor Sanchez-Martinez, and Javier A. Menendez
Subjects: metformin, SIRT1, aging, NAD+, NAD loss, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Metformin has been proposed to operate as an agonist of SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that mimics most of the metabolic responses to calorie restriction. Herein, we present an in silico analysis focusing on the molecular docking and dynamic simulation of the putative interactions between metformin and SIRT1. Using eight different crystal structures of human SIRT1 protein, our computational approach was able to delineate the putative binding modes of metformin to several pockets inside and outside the central deacetylase catalytic domain. First, metformin was predicted to interact with the very same allosteric site occupied by resveratrol and other sirtuin-activating compounds (STATCs) at the amino-terminal activation domain of SIRT1. Second, metformin was predicted to interact with the NAD+ binding site in a manner slightly different to that of SIRT1 inhibitors containing an indole ring. Third, metformin was predicted to interact with the C-terminal regulatory segment of SIRT1 bound to the NAD+ hydrolysis product ADP-ribose, a “C-pocket”-related mechanism that appears to be essential for mechanism-based activation of SIRT1. Enzymatic assays confirmed that the net biochemical effect of metformin and other biguanides such as a phenformin was to improve the catalytic efficiency of SIRT1 operating in conditions of low NAD+ in vitro. Forthcoming studies should confirm the mechanistic relevance of our computational insights into how the putative binding modes of metformin to SIRT1 could explain its ability to operate as a direct SIRT1-activating compound. These findings might have important implications for understanding how metformin might confer health benefits via maintenance of SIRT1 activity during the aging process when NAD+ levels decline.
Published: 2018
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21. Coupling Machine Learning and Lipidomics as a Tool to Investigate Metabolic Dysfunction-Associated Fatty Liver Disease. A General Overview

Author: Helena Castañé, Gerard Baiges-Gaya, Anna Hernández-Aguilera, Elisabet Rodríguez-Tomàs, Salvador Fernández-Arroyo, Pol Herrero, Antoni Delpino-Rius, Nuria Canela, Javier A. Menendez, Jordi Camps, and Jorge Joven
Subjects: adipose tissue, artificial intelligence, bariatric surgery, deep learning, metabolism, NASH, Microbiology, QR1-502
Abstract: Hepatic biopsy is the gold standard for staging nonalcoholic fatty liver disease (NAFLD). Unfortunately, accessing the liver is invasive, requires a multidisciplinary team and is too expensive to be conducted on large segments of the population. NAFLD starts quietly and can progress until liver damage is irreversible. Given this complex situation, the search for noninvasive alternatives is clinically important. A hallmark of NAFLD progression is the dysregulation in lipid metabolism. In this context, recent advances in the area of machine learning have increased the interest in evaluating whether multi-omics data analysis performed on peripheral blood can enhance human interpretation. In the present review, we show how the use of machine learning can identify sets of lipids as predictive biomarkers of NAFLD progression. This approach could potentially help clinicians to improve the diagnosis accuracy and predict the future risk of the disease. While NAFLD has no effective treatment yet, the key to slowing the progression of the disease may lie in predictive robust biomarkers. Hence, to detect this disease as soon as possible, the use of computational science can help us to make a more accurate and reliable diagnosis. We aimed to provide a general overview for all readers interested in implementing these methods.
Published: 2021
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22. Binding of the angiogenic/senescence inducer CCN1/CYR61 to integrin α6β1 drives endocrine resistance in breast cancer cells

Author: Ingrid Espinoza, Lin Yang, Travis Vander Steen, Luciano Vellon, Elisabet Cuyàs, Sara Verdura, Lester Lau, Javier A. Menendez, and Ruth Lupu
Subjects: Aging, Quimioreceptors, Chemoreceptors, Estrògens -- Receptors, Estrogen -- Receptors, Breast -- Cancer -- Endocrine aspects, Breast -- Cancer -- Treatment, Cell Biology, Mama -- Càncer -- Tractament, Mama -- Càncer -- Aspectes endocrins
Abstract: CCN1/CYR61 promotes angiogenesis, tumor growth and chemoresistance by binding to its integrin receptor αvβ3 in endothelial and breast cancer (BC) cells. CCN1 controls also tissue regeneration by engaging its integrin receptor α6β1 to induce fibroblast senescence. Here, we explored if the ability of CCN1 to drive an endocrine resistance phenotype in estrogen receptor-positive BC cells relies on interactions with either αvβ3 or α6β1. First, we took advantage of site-specific mutagenesis abolishing the CCN1 receptor-binding sites to αvβ3 and α6β1 to determine the integrin partner responsible for CCN1-driven endocrine resistance. Second, we explored a putative nuclear role of CCN1 in regulating ERα-driven transcriptional responses. Retroviral forced expression of a CCN1 derivative with a single amino acid change (D125A) that abrogates binding to αvβ3 partially phenocopied the endocrine resistance phenotype induced upon overexpression of wild-type (WT) CCN1. Forced expression of the CCN1 mutant TM, which abrogates all the T1, H1, and H2 binding sites to α6β1, failed to bypass the estrogen requirement for anchorage-independent growth or to promote resistance to tamoxifen. Wild-type CCN1 promoted estradiolindependent transcriptional activity of ERα and enhanced ERα agonist response to tamoxifen. The α6β1-bindingdefective TM-CCN1 mutant lost the ERα co-activator-like behavior of WT-CCN1. Co-immunoprecipitation assays revealed a direct interaction between endogenous CCN1 and ERα, and in vitro approaches confirmed the ability of recombinant CCN1 to bind ERα. CCN1 signaling via α6β1, but not via αvβ3, drives an endocrine resistance phenotype that involves a direct binding of CCN1 to ERα to regulate itstranscriptional activity in ER+ BC cells
Published: 2022

23. Oncometabolic Nuclear Reprogramming of Cancer Stemness

Author: Javier A. Menendez, Bruna Corominas-Faja, Elisabet Cuyàs, María G. García, Salvador Fernández-Arroyo, Agustín F. Fernández, Jorge Joven, Mario F. Fraga, and Tomás Alarcón
Subjects: Oncometabolites, reprogramming, stemness, cancer, stem cells, cancer stem cells, Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract: By impairing histone demethylation and locking cells into a reprogramming-prone state, oncometabolites can partially mimic the process of induced pluripotent stem cell generation. Using a systems biology approach, combining mathematical modeling, computation, and proof-of-concept studies with live cells, we found that an oncometabolite-driven pathological version of nuclear reprogramming increases the speed and efficiency of dedifferentiating committed epithelial cells into stem-like states with only a minimal core of stemness transcription factors. Our biomathematical model, which introduces nucleosome modification and epigenetic regulation of cell differentiation genes to account for the direct effects of oncometabolites on nuclear reprogramming, demonstrates that oncometabolites markedly lower the “energy barriers” separating non-stem and stem cell attractors, diminishes the average time of nuclear reprogramming, and increases the size of the basin of attraction of the macrostate occupied by stem cells. These findings establish the concept of oncometabolic nuclear reprogramming of stemness as a bona fide metabolo-epigenetic mechanism for generation of cancer stem-like cells.
Published: 2016
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24. Metabolomic and Mitochondrial Fingerprinting of the Epithelial-to-Mesenchymal Transition (EMT) in Non-Tumorigenic and Tumorigenic Human Breast Cells

Author: Elisabet Cuyàs, Salvador Fernández-Arroyo, Sara Verdura, Ruth Lupu, Jorge Joven, and Javier A. Menendez
Subjects: metabolism, mitochondria, phenotypic screening, breast cancer, therapy resistance, complex III, Cancer Research, Oncology
Abstract: Epithelial-to-mesenchymal transition (EMT) is key to tumor aggressiveness, therapy resistance, and immune escape in breast cancer. Because metabolic traits might be involved along the EMT continuum, we investigated whether human breast epithelial cells engineered to stably acquire a mesenchymal phenotype in non-tumorigenic and H-RasV12-driven tumorigenic backgrounds possess unique metabolic fingerprints. We profiled mitochondrial–cytosolic bioenergetic and one-carbon (1C) metabolites by metabolomic analysis, and then questioned the utilization of different mitochondrial substrates by EMT mitochondria and their sensitivity to mitochondria-centered inhibitors. “Upper” and “lower” glycolysis were the preferred glucose fluxes activated by EMT in non-tumorigenic and tumorigenic backgrounds, respectively. EMT in non-tumorigenic and tumorigenic backgrounds could be distinguished by the differential contribution of the homocysteine-methionine 1C cycle to the transsulfuration pathway. Both non-tumorigenic and tumorigenic EMT-activated cells showed elevated mitochondrial utilization of glycolysis end-products such as lactic acid, β-oxidation substrates including palmitoyl–carnitine, and tricarboxylic acid pathway substrates such as succinic acid. Notably, mitochondria in tumorigenic EMT cells distinctively exhibited a significant alteration in the electron flow intensity from succinate to mitochondrial complex III as they were highly refractory to the inhibitory effects of antimycin A and myxothiazol. Our results show that the bioenergetic/1C metabolic signature, the utilization rates of preferred mitochondrial substrates, and sensitivity to mitochondrial drugs significantly differs upon execution of EMT in non-tumorigenic and tumorigenic backgrounds, which could help to resolve the relationship between EMT, malignancy, and therapeutic resistance in breast cancer.
Published: 2022
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25. Silibinin Overcomes EMT-Driven Lung Cancer Resistance to New-Generation ALK Inhibitors

Author: Sara Verdura, Jose Antonio Encinar, Eduard Teixidor, Antonio Segura-Carretero, Vicente Micol, Elisabet Cuyàs, Joaquim Bosch-Barrera, and Javier A. Menendez
Subjects: Cancer Research, Lorlatinib, Oncology, ALK, Crizotinib, Brigatinib, Silibinin, crizotinib, brigatinib, lorlatinib, silibinin, EMT, TGFβ, lung cancer, TGF-beta, Lung cancer
Abstract: Epithelial-to-mesenchymal transition (EMT) may drive the escape of ALK-rearranged non-small-cell lung cancer (NSCLC) tumors from ALK-tyrosine kinase inhibitors (TKIs). We investigated whether first-generation ALK–TKI therapy-induced EMT promotes cross-resistance to new-generation ALK–TKIs and whether this could be circumvented by the flavonolignan silibinin, an EMT inhibitor. ALK-rearranged NSCLC cells acquiring a bona fide EMT phenotype upon chronic exposure to the first-generation ALK–TKI crizotinib exhibited increased resistance to secondgeneration brigatinib and were fully refractory to third-generation lorlatinib. Such cross-resistance to new-generation ALK–TKIs, which was partially recapitulated upon chronic TGF stimulation, was less pronounced in ALK-rearranged NSCLC cells solely acquiring a partial/hybrid E/M transition state. Silibinin overcame EMT-induced resistance to brigatinib and lorlatinib and restored their efficacy involving the transforming growth factor-beta (TGF )/SMAD signaling pathway. Silibinin deactivated TGF -regulated SMAD2/3 phosphorylation and suppressed the transcriptional activation of genes under the control of SMAD binding elements. Computational modeling studies and kinase binding assays predicted a targeted inhibitory binding of silibinin to the ATP-binding pocket of TGF type-1 receptor 1 (TGFBR1) and TGFBR2 but solely at the two-digit micromolar range. A secretome profiling confirmed the ability of silibinin to normalize the augmented release of TGF into the extracellular fluid of ALK–TKIs-resistant NSCLC cells and reduce constitutive and inducible SMAD2/3 phosphorylation occurring in the presence of ALK–TKIs. In summary, the ab initio plasticity along the EMT spectrum may explain the propensity of ALK-rearranged NSCLC cells to acquire resistance to new-generation ALK–TKIs, a phenomenon that could be abrogated by the silibinin-driven attenuation of the TGF /SMAD signaling axis in mesenchymal ALK-rearranged NSCLC cells., Ministry of Science and Innovation, Spain (MICINN) Spanish Government, Plan Nacional de l+D+I PID2019-10455GB-I00 CP20/00003 Spanish Government, Fundacio Oncolliga Girona (Lliga catalana d'ajuda al malalt de cancer, Girona), Spanish Government, Center for Forestry Research & Experimentation (CIEF), European Commission PI22/00297, Grupo Espanol de Cancer de Pulmon (GECP) RTI2019-096724-B-C21, La Marato de TV3 foundation, Health Research and Innovation Strategic Plan PROMETEO/2021/059, Pla strategic de recerca i innovacio en salut 201906, Generalitat de Catalunya, Instituto de Salud Carlos III SLT006/17/114
Published: 2022

26. Circulating levels of MOTS-c in patients with breast cancer treated with metformin

Author: Elisabet, Cuyàs, Sara, Verdura, Begoña, Martin-Castillo, and Javier A, Menendez
Subjects: Aging, Cell Biology
Abstract: The mitokine MOTS-c is a mitochondrially-encoded "exercise-mimetic peptide" expressed in multiple tissues, particularly skeletal muscles, which can be detected as a circulating hormone in the blood. MOTS-c mechanisms of action (MoA) involve insulin sensitization, enhanced glucose utilization, suppression of mitochondrial respiration, and targeting of the folate-AICAR-AMPK pathway. Although MOTS-c MoA largely overlap those of the anti-diabetic biguanide metformin, the putative regulatory actions of metformin on MOTS-c have not yet been evaluated in detail. Here, we measured circulating MOTS-c in paired baseline and post-treatment sera obtained from HER2-positive breast cancer patients randomized to receive either metformin combined with neoadjuvant chemotherapy and trastuzumab or an equivalent regimen without metformin. We failed to find any significant alteration of circulating MOTS-c -as measured using the commercially available competitive ELISA CEX132Hu- in response to 24 weeks of a neoadjuvant chemotherapy/trastuzumab regimen with or without daily metformin. Changes in circulating MOTS-c levels failed to reach statistical significance when comparing patients achieving pathological complete response (pCR), irrespective of metformin treatment. The inability of metformin to target skeletal muscle, the major tissue for MOTS-c production and secretion, might limit its regulatory effects on circulating MOTS-c. Further studies are needed to definitely elucidate the nature of the interaction between metformin and MOTS-c in cancer and non-cancer patients.
Published: 2022

27. Heregulin Drives Endocrine Resistance by Altering IL-8 Expression in ER-Positive Breast Cancer

Author: Adriana Papadimitropoulou, Luciano Vellon, Ella Atlas, Travis Vander Steen, Elisabet Cuyàs, Sara Verdura, Ingrid Espinoza, Javier A. Menendez, and Ruth Lupu
Subjects: cytokines, IL-8, tamoxifen, autocrine, luminal, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Sustained HER2/HER3 signaling due to the overproduction of the HER3 ligand heregulin (HRG) is proposed as a key contributor to endocrine resistance in estrogen receptor-positive (ER+) breast cancer. The molecular mechanisms linking HER2 transactivation by HRG-bound HER3 to the acquisition of a hormone-independent phenotype in ER+ breast cancer is, however, largely unknown. Here, we explored the possibility that autocrine HRG signaling drives cytokine-related endocrine resistance in ER+ breast cancer cells. We used human cytokine antibody arrays to semi-quantitatively measure the expression level of 60 cytokines and growth factors in the extracellular milieu of MCF-7 cells engineered to overexpress full-length HRGβ2 (MCF-7/HRG cells). Interleukin-8 (IL-8), a chemokine closely linked to ER inaction, emerged as one the most differentially expressed cytokines. Cytokine profiling using structural deletion mutants lacking both the N-terminus and the cytoplasmic-transmembrane region of HRGβ2—which is not secreted and cannot transactivate HER2—or lacking a nuclear localization signal at the N-terminus—which cannot localize at the nucleus but is actively secreted and transactivates HER2—revealed that the HRG-driven activation of IL-8 expression in ER+ cells required HRG secretion and transactivation of HER2 but not HRG nuclear localization. The functional blockade of IL-8 with a specific antibody inversely regulated ERα-driven transcriptional activation in endocrine-sensitive MCF-7 cells and endocrine-resistant MCF-7/HRG cells. Overall, these findings suggest that IL-8 participates in the HRG-driven endocrine resistance program in ER+/HER2- breast cancer and might illuminate a potential clinical setting for IL8- or CXCR1/2-neutralizing antibodies.
Published: 2020
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28. Fatty Acid Synthase Is a Key Enabler for Endocrine Resistance in Heregulin-Overexpressing Luminal B-Like Breast Cancer

Author: Javier A. Menendez, Inderjit Mehmi, Adriana Papadimitropoulou, Travis Vander Steen, Elisabet Cuyàs, Sara Verdura, Ingrid Espinoza, Luciano Vellon, Ella Atlas, and Ruth Lupu
Subjects: luminal, tamoxifen, fulvestrant, endocrine resistance, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: HER2 transactivation by the HER3 ligand heregulin (HRG) promotes an endocrine-resistant phenotype in the estrogen receptor-positive (ER+) luminal-B subtype of breast cancer. The underlying biological mechanisms that link them are, however, incompletely understood. Here, we evaluated the putative role of the lipogenic enzyme fatty acid synthase (FASN) as a major cause of HRG-driven endocrine resistance in ER+/HER2-negative breast cancer cells. MCF-7 cells engineered to stably overexpress HRG (MCF-7/HRG), an in vitro model of tamoxifen/fulvestrant-resistant luminal B-like breast cancer, showed a pronounced up-regulation of FASN gene/FASN protein expression. Autocrine HRG up-regulated FASN expression via HER2 transactivation and downstream activation of PI-3K/AKT and MAPK-ERK1/2 signaling pathways. The HRG-driven FASN-overexpressing phenotype was fully prevented in MCF-7 cells expressing a structural deletion mutant of HRG that is sequestered in a cellular compartment and lacks the ability to promote endocrine-resistance in an autocrine manner. Pharmacological inhibition of FASN activity blocked the estradiol-independent and tamoxifen/fulvestrant-refractory ability of MCF-7/HRG cells to anchorage-independently grow in soft-agar. In vivo treatment with a FASN inhibitor restored the anti-tumor activity of tamoxifen and fulvestrant against fast-growing, hormone-resistant MCF-7/HRG xenograft tumors in mice. Overall, these findings implicate FASN as a key enabler for endocrine resistance in HRG+/HER2- breast cancer and highlight the therapeutic potential of FASN inhibitors for the treatment of endocrine therapy-resistant luminal-B breast cancer.
Published: 2020
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29. Potential Drugs Targeting Early Innate Immune Evasion of SARS-Coronavirus 2 via 2’-O-Methylation of Viral RNA

Author: José Antonio Encinar and Javier A. Menendez
Subjects: COVID-19, drug repurposing, methylation, methyltransferases, computational screening, molecular docking, Microbiology, QR1-502
Abstract: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causing the COVID-19 respiratory disease pandemic utilizes unique 2′-O-methyltransferase (2′-O-MTase) capping machinery to camouflage its RNA from innate immune recognition. The nsp16 catalytic subunit of the 2′-O-MTase is unusual in its requirement for a stimulatory subunit (nsp10) to catalyze the ribose 2′-O-methylation of the viral RNA cap. Here we provide a computational basis for drug repositioning or de novo drug development based on three differential traits of the intermolecular interactions of the SARS-CoV-2-specific nsp16/nsp10 heterodimer, namely: (1) the S-adenosyl-l-methionine-binding pocket of nsp16, (2) the unique “activating surface” between nsp16 and nsp10, and (3) the RNA-binding groove of nsp16. We employed ≈9000 U.S. Food and Drug Administration (FDA)-approved investigational and experimental drugs from the DrugBank repository for docking virtual screening. After molecular dynamics calculations of the stability of the binding modes of high-scoring nsp16/nsp10–drug complexes, we considered their pharmacological overlapping with functional modules of the virus–host interactome that is relevant to the viral lifecycle, and to the clinical features of COVID-19. Some of the predicted drugs (e.g., tegobuvir, sonidegib, siramesine, antrafenine, bemcentinib, itacitinib, or phthalocyanine) might be suitable for repurposing to pharmacologically reactivate innate immune restriction and antagonism of SARS-CoV-2 RNAs lacking 2′-O-methylation.
Published: 2020
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30. Metformin: Sentinel of the Epigenetic Landscapes That Underlie Cell Fate and Identity

Author: Javier A. Menendez
Subjects: aging, cancer, epigenetics, DNA, histones, methylation, Microbiology, QR1-502
Abstract: The biguanide metformin is the first drug to be tested as a gerotherapeutic in the clinical trial TAME (Targeting Aging with Metformin). The current consensus is that metformin exerts indirect pleiotropy on core metabolic hallmarks of aging, such as the insulin/insulin-like growth factor 1 and AMP-activated protein kinase/mammalian Target Of Rapamycin signaling pathways, downstream of its primary inhibitory effect on mitochondrial respiratory complex I. Alternatively, but not mutually exclusive, metformin can exert regulatory effects on components of the biologic machinery of aging itself such as chromatin-modifying enzymes. An integrative metabolo-epigenetic outlook supports a new model whereby metformin operates as a guardian of cell identity, capable of retarding cellular aging by preventing the loss of the information-theoretic nature of the epigenome. The ultimate anti-aging mechanism of metformin might involve the global preservation of the epigenome architecture, thereby ensuring cell fate commitment and phenotypic outcomes despite the challenging effects of aging noise. Metformin might therefore inspire the development of new gerotherapeutics capable of preserving the epigenome architecture for cell identity. Such gerotherapeutics should replicate the ability of metformin to halt the erosion of the epigenetic landscape, mitigate the loss of cell fate commitment, delay stochastic/environmental DNA methylation drifts, and alleviate cellular senescence. Yet, it remains a challenge to confirm if regulatory changes in higher-order genomic organizers can connect the capacity of metformin to dynamically regulate the three-dimensional nature of epigenetic landscapes with the 4th dimension, the aging time.
Published: 2020
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31. Plasma Energy-Balance Metabolites Discriminate Asymptomatic Patients with Peripheral Artery Disease

Author: Anna Hernández-Aguilera, Salvador Fernández-Arroyo, Noemí Cabre, Fedra Luciano-Mateo, Gerard Baiges-Gaya, Montserrat Fibla, Vicente Martín-Paredero, Javier A. Menendez, Jordi Camps, and Jorge Joven
Subjects: Pathology, RB1-214
Abstract: Peripheral artery disease (PAD) is a common disease affecting 20–25% of population over 60 years old. Early diagnosis is difficult because symptoms only become evident in advanced stages of the disease. Inflammation, impaired metabolism, and mitochondrial dysfunction predispose to PAD, which is normally associated with other highly prevalent and related conditions, such as diabetes, dyslipidemia, and hypertension. We have measured energy-balance-associated metabolite concentrations in the plasma of PAD patients segregated by the severity of the disease and in plasma of healthy volunteers using a quantitative and targeted metabolomic approach. We found relevant associations between several metabolites (3-hydroxybutirate, aconitate, (iso)citrate, glutamate, and serine) with markers of oxidative stress and inflammation. Metabolomic profiling also revealed that (iso)citrate and glutamate are metabolites with high ability to discriminate between healthy participants and PAD patients without symptoms. Collectively, our data suggest that metabolomics provide significant information on the pathogenesis of PAD and useful biomarkers for the diagnosis and assessment of progression.
Published: 2018
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32. Optimization of a GC-MS Injection-Port Derivatization Methodology to Enhance Metabolomics Analysis Throughput in Biological Samples

Author: Elisabet Foguet-Romero, Iris Samarra, Maria Guirro, Marc Riu, Jorge Joven, Javier A. Menendez, Núria Canela, Antoni DelPino-Rius, Salvador Fernández-Arroyo, and Pol Herrero
Subjects: Humans, Metabolomics, Indicators and Reagents, General Chemistry, Amino Acids, Biochemistry, Acids, Gas Chromatography-Mass Spectrometry
Abstract: Advances in metabolomics analysis and data treatment increase the knowledge of complex biological systems. One of the most used methodologies is gas chromatography-mass spectrometry (GC-MS) due to its robustness, high separation efficiency, and reliable peak identification through curated databases. However, methodologies are not standardized, and the derivatization steps in GC-MS can introduce experimental errors and take considerable time, exposing the samples to degradation. Here, we propose the injection-port derivatization (IPD) methodology to increase the throughput in plasma metabolomics analysis by GC-MS. The IPD method was evaluated and optimized for different families of metabolites (organic acids, amino acids, fatty acids, sugars, sugar phosphates, etc.) in terms of residence time, injection-port temperature, and sample/derivatization reagent ratio. Finally, the method's usefulness was validated in a study consisting of a cohort of obese patients with or without nonalcoholic steatohepatitis. Our results show a fast, reproducible, precise, and reliable method for the analysis of biological samples by GC-MS. Raw data are publicly available at MetaboLights with Study Identifier MTBLS5151.
Published: 2022

33. Senescence-Inflammatory Regulation of Reparative Cellular Reprogramming in Aging and Cancer

Author: Javier A. Menendez and Tomás Alarcón
Subjects: reprogramming, aging, cancer, senescence, inflammation, Biology (General), QH301-705.5
Abstract: The inability of adult tissues to transitorily generate cells with functional stem cell-like properties is a major obstacle to tissue self-repair. Nuclear reprogramming-like phenomena that induce a transient acquisition of epigenetic plasticity and phenotype malleability may constitute a reparative route through which human tissues respond to injury, stress, and disease. However, tissue rejuvenation should involve not only the transient epigenetic reprogramming of differentiated cells, but also the committed re-acquisition of the original or alternative committed cell fate. Chronic or unrestrained epigenetic plasticity would drive aging phenotypes by impairing the repair or the replacement of damaged cells; such uncontrolled phenomena of in vivo reprogramming might also generate cancer-like cellular states. We herein propose that the ability of senescence-associated inflammatory signaling to regulate in vivo reprogramming cycles of tissue repair outlines a threshold model of aging and cancer. The degree of senescence/inflammation-associated deviation from the homeostatic state may delineate a type of thresholding algorithm distinguishing beneficial from deleterious effects of in vivo reprogramming. First, transient activation of NF-κB-related innate immunity and senescence-associated inflammatory components (e.g., IL-6) might facilitate reparative cellular reprogramming in response to acute inflammatory events. Second, para-inflammation switches might promote long-lasting but reversible refractoriness to reparative cellular reprogramming. Third, chronic senescence-associated inflammatory signaling might lock cells in highly plastic epigenetic states disabled for reparative differentiation. The consideration of a cellular reprogramming-centered view of epigenetic plasticity as a fundamental element of a tissue's capacity to undergo successful repair, aging degeneration or malignant transformation should provide challenging stochastic insights into the current deterministic genetic paradigm for most chronic diseases, thereby increasing the spectrum of therapeutic approaches for physiological aging and cancer.
Published: 2017
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34. Search for resonances decaying to three W bosons in the hadronic final state in proton-proton collisions at s=13 TeV

Author: Viacheslav Bunichev, Mikko Voutilainen, Jordan Nash, Dmitry Kondratyev, Francisco Garcia, Raghunath Pradhan, Gabriella Pugliese, Alberto Escalante del Valle, Praveen Chandra Tiwari, Mate Csanad, Kadir Saygin, Kenneth Bloom, Pietro Govoni, Maximilian Pérez Prada, Arie Bodek, Riccardo Salvatico, Mikhail Dubinin, Andrea Cardini, Chang-Seong Moon, Ted Kolberg, Guenakh Mitselmakher, Kun Shi, Caglar Zorbilmez, Lorenzo Viliani, Ankush Reddy Kanuganti, Wesley Smith, Mikael Myllymäki, Walaa Elmetenawee, Erhan Gülmez, Giovanni Abbiendi, Fabrizio Palla, Valentina Sola, Matthias Schröder, Cristina Riccardi, Johan Borg, Sami Lehti, Abanti Ranadhir Sahasransu, Joseph Reichert, Jussi Viinikainen, Badder Marzocchi, Luke Kreczko, Hugues Lattaud, FLAVIA CETORELLI, Georgios Konstantinos Krintiras, Samet Lezki, Stefano Belforte, Maria Savina, Reza Goldouzian, Márton Bartók, Daniele Fasanella, Erika Garutti, Louis Moureaux, Nadia Pastrone, Danyer Pérez Adán, Muhammad Ahmad, Konstantin Androsov, Toni Sculac, Arun Kumar, Andreas Pfeiffer, Jorge Berenguer Antequera, Giuseppe Della Ricca, Eduard De La Cruz Burelo, Joern Schwandt, Christopher Tully, Luigi Calligaris, Wael HAJ AHMAD (Vael HAJAHMAD), Jennifer Ott, Francisco Javier Cuevas Maestro, Steffen Albrecht, Pablo Matorras-Cuevas, Prabhat Ranjan Pujahari, Alessandra Cappati, Alexander Belyaev, Florian Bury, Roman Kogler, Andrea Giammanco, Marco Toliman Lucchini, Guenther Dissertori, Francesca Cavallari, José María Hernández Calama, Efe Yazgan, Nils Faltermann, Yuri Gershtein, Sinan Sagir, Tomas Lindén, Halil Saka, Luca Cadamuro, Florencia Canelli, Simone Pigazzini, Armando Bermudez Martinez, Dmitri Konstantinov, Ksenia Shchelina, Cesar Augusto Bernardes, Bingran Wang, Qiang Li, Nicolò Trevisani, Tapio Lampén, Md Naimuddin, Barry Blumenfeld, Leonid Levchuk, Claudio Grandi, Giovanni Petrucciani, Dayong Wang, Marco Zanetti, Cristina Botta, Danilo Meuser, Martti Raidal, John Conway, Jaime Leon Holgado, Paolo Giacomelli, Jay R. Dittmann, Yalcin Guler, Agni Bethani, Marcin Konecki, Franco Ligabue, Alexander Grohsjean, Lourdes Urda, Mahmoud Moussa Abdelkhalek Gadallah, Silvano Tosi, Martina Malberti, Merve Ince Lezki, Jochen Schieck, Leonardo Cristella, Ernesto Migliore, Pritam Kalbhor, Silvia Goy Lopez, Ashish Sharma, Tommaso Diotalevi, Nikolaos Manthos, Lisa Benato, Suman Chatterjee, Émilien Chapon, JUAN ALCARAZ MAESTRE, Antonio Vilela Pereira, Álvaro Navarro-Tobar, Thong Q. Nguyen, Zhenbin Wu, Maria Clemencia Mora Herrera, Zhengyun You, Agostino De Iorio, Ilaria Vai, Gilvan Alves, Sandeep Bhowmik, Cristina Fernández Bedoya, Nabin Poudyal, Markus Seidel, Andre Sznajder, Ali Eren Simsek, Tamer Elkafrawy, Pedro Galli Mercadante, Kenyi Hurtado Anampa, Luca Giommi, Efe Yigitbasi, Andrea Massironi, Andrey Starodumov, Jose Ruiz, Mario Pelliccioni, Caroline Collard, Alexei Safonov, WILLIAM FORD, Junghwan Goh, Spandan Mondal, Jingyan Li, German Ruben Martinez, Walter Snoeys, Evgueni Tcherniaev, Matteo Presilla, Stephen Mrenna, Jeremy Andrea, Panja Luukka, Saranya Samik Ghosh, Rogelio Reyes-Almanza, Joachim Mnich, Sandor Lokos, Darin Acosta, Karl Ehatäht, Aurelijus Rinkevicius, Frank Geurts, Isabel Josa Mutuberria, Junquan Tao, Paul Kyberd, Ece ASILAR, David D'Enterria, Daniel Savoiu, Francesco Fienga, Jay Lawhorn, Arabella Martelli, Robert Cousins, Santeri Laurila, Jorma Tuominiemi, Andrey Popov, Jehad Mousa, Martin Grunewald, Paolo Spagnolo, Nicholas Wardle, Redwan Habibullah, Robert Klanner, Frank Golf, Isidro González Caballero, Crisostomo Sciacca, Oscar Gonzalez Lopez, Tahys Janssen, Jeremi Niedziela, Robert Bainbridge, Elizabeth Starling, Andrea Rizzi, Javier Alberto Murillo Quijada, Klaus Rabbertz, Luigi (Gigi) Rolandi, Federica Legger, Andrew Ivanov, ANKITA MEHTA, Ioannis Papadopoulos, Greg Landsberg, Malte Backhaus, Aliakbar Ebrahimi, INSEOK YOON, Sara Fiorendi, ANDREA PICCINELLI, Dmitry Kirpichnikov, Jennifer Ngadiuba, Tamas Almos Vami, Ivan Heredia de la Cruz, Maciej Malawski, Vuko Brigljević, Thomas McCauley, Vittorio Raoul Tavolaro, Pablo Martinez Ruiz del Arbol, Davide Fiorina, Kaur Sandeep, Reddy Pratap Gandrajula, Luca Malgeri, Leszek Grzanka, Peter Elmer, Lea Caminada, Kenneth Osterberg, Leandar Litov, Lata Panwar, Zhicai Zhang, Anton Stepennov, Arnd Meyer, Tatyana Dimova, Christophe Ochando, Alberto Ruiz Jimeno, J B Singh, Johannes Lange, Peter Wittich, Maria Cruz Fouz Iglesias, Korbinian Schweiger, Gaetano Marco Dallavalle, Pietro Faccioli, Rafael Eduardo Sosa Ricardo, Avi Yagil, Muhammad Gul, Jaana Heikkilä, Arne Christoph Reimers, Michele Arneodo, José Flix Molina, Javier Fernandez Menendez, Alexander Tapper, Valeria D'Amante, Sandra S. Padula, George Alverson, Lev Dudko, Juan Pablo Fernández Ramos, Karl Ecklund, Salvatore Costa, Yacine Haddad, Carlos Eugenio Perez Lara, Paolo Meridiani, Ignacio Redondo, Marco Monteno, Gautier Hamel de Monchenault, Salvatore Rappoccio, Gerrit Van Onsem, Thomas Reis, Anna Colaleo, Marco CUFFIANI, Torben Lange, Lutz Feld, Varun Sharma, Gabriella Pásztor, Nicolas Stylianou, Sung-Won Lee, Joel Goldstein, Daniel Diaz, Paolo Azzurri, Oleg Filatov, Welathantri Dharmaratna, ÜMİT SÖZBİLİR, Davide Zuolo, Ram Krishna Sharma, Ian Watson, Javier Mauricio Duarte, Vilius Cepaitis, Andreas Hinzmann, Nikkie Deelen, Matthias Kasemann, Manfred Paulini, Paolo Dini, Andre Frankenthal, Kevin Lannon, Mithat Kaya, Florian Beaudette, Barbara Alvarez Gonzalez, Nuno Leonardo, Maxim Titov, Laurent Forthomme, Jose Enrique Palencia Cortezon, Rainer Wallny, Pietro Vischia, Schoefbeck Robert, Thea Aarrestad, Gaia Grosso, Pieter David, Liuyao Zhang, Tae Jeong Kim, Marco Pieri, Sunil Manohar Dogra, Shabnam Jabeen, Guido Emilio Tonelli, Mar Capeans, Davide Di Croce, Ugur Kiminsu, J.F. Benitez, Luiz Mundim, Jason Lee, Maria Cepeda, Pallabi Das, Ksenia De Leo, Deborah Pinna, Morgan Lethuillier, Soureek Mitra, Bruno Lenzi, Sergio Novaes, Antonio Delgado Peris, Amina Zghiche, Pieter Everaerts, Gurpreet Singh Chahal, Hannu Siikonen, Mohammed Attia Mahmoud, André David Tinoco Mendes, Olga Evdokimov, Pierluigi Bortignon, Shubhanshu Chauhan, Simone Gennai, Freya Blekman, Furkan Dolek, Umberto Dosselli, Federica Maria Simone, Raffaele Gerosa, Benjamin Krikler, Geoffrey Hall, Eija Tuominen, Marko Dragicevic, Antonio Perez-Calero Yzquierdo, Nadezda Chernyavskaya, Mykhailo Dalchenko, Joona Juhani Havukainen, Biagio Rossi, Ibrahim Soner Zorbakir, Sandra Consuegra Rodriguez, Roberto Covarelli, Chiara Amendola, Christophorus Grab, Mojtaba Mohammadi Najafabadi, Henning Flaecher, Dilson De Jesus Damiao, Arthur Moraes, Lucas Taylor, Graham Wilson, Rui Xiao, Minsuk Kim, Alberto Sanchez-Hernandez, Tobias Robert Jakob Kramer, Marino Missiroli, Jan-Frederik Schulte, Fotios Ptochos, Shudhashil Bharthuar, Justin Williams, Helen Heath, Wolfgang Waltenberger, Henning Kirschenmann, Hannes Jung, Emrah Tiras, Camilo Carrillo Montoya, Yu Zhang, Alberto Zucchetta, Ralf Ulrich, Calandri Alessandro, Tahereh Sadat Niknejad, Guillelmo Gomez-Ceballos, Felipe Araujo, Kadri Ozdemir, Patrizia Azzi, Muhammad Alibordi, Vladimir Gavrilov, Johannes Haller, Kati Lassila-Perini, Abhijith Gandrakota, Konstantinos Theofilatos, Gouranga Kole, Eliza Melo da Costa, Andrea Davide Benaglia, Sebastian Wuchterl, Jesus Puerta Pelayo, Laura Martikainen, Ram Krishna Dewanjee, Christophe Delaere, Simon Regnard, Aaron Dominguez, Emanuele Usai, Matthew Herndon, Kenichi Hatakeyama, LUCA GUZZI, Alberto Belloni, Harrison Bertrand Prosper, Federico Siviero, Mariana Shopova, Mauro Donega, Abideh Jafari, Antonio Cassese, Federico De Guio, UTTIYA SARKAR, Aashaq Shah, Oliver Gutsche, Claudio Caputo, Mauro Emanuele Dinardo, Elisabetta Manca, Amedeo Staiano, Soumya Mukherjee, Thiago Rafael Fernandez Perez Tomei, Sudhir Malik, Clemens Lange, and Bożena Boimska
Published: 2022

35. Search for Resonances Decaying to Three W Bosons in Proton-Proton Collisions at s=13 TeV

Author: Viacheslav Bunichev, Mikko Voutilainen, Stefaan Tavernier, Jordan Nash, Francisco Garcia, Raghunath Pradhan, Gabriella Pugliese, Alberto Escalante del Valle, Praveen Chandra Tiwari, Mate Csanad, Kadir Saygin, Kenneth Bloom, Pietro Govoni, Maximilian Pérez Prada, Arie Bodek, Riccardo Salvatico, Mikhail Dubinin, Andrea Cardini, Chang-Seong Moon, Ted Kolberg, Guenakh Mitselmakher, Kun Shi, Caglar Zorbilmez, Lorenzo Viliani, Ankush Reddy Kanuganti, Wesley Smith, Mikael Myllymäki, Hesham El Faham, Walaa Elmetenawee, Erhan Gülmez, Giovanni Abbiendi, Fabrizio Palla, Valentina Sola, Matthias Schröder, Cristina Riccardi, Sami Lehti, Abanti Ranadhir Sahasransu, Joseph Reichert, Jussi Viinikainen, Badder Marzocchi, Luke Kreczko, Hugues Lattaud, FLAVIA CETORELLI, Georgios Konstantinos Krintiras, Samet Lezki, Stefano Belforte, Maria Savina, Reza Goldouzian, Márton Bartók, Daniele Fasanella, Erika Garutti, Shalini Thakur, Louis Moureaux, Nadia Pastrone, Danyer Pérez Adán, Muhammad Ahmad, Konstantin Androsov, Toni Sculac, Arun Kumar, Andreas Pfeiffer, Jorge Berenguer Antequera, Giuseppe Della Ricca, Eduard De La Cruz Burelo, Joern Schwandt, Christopher Tully, Luigi Calligaris, Wael HAJ AHMAD (Vael HAJAHMAD), Jennifer Ott, Francisco Javier Cuevas Maestro, Steffen Albrecht, Pablo Matorras-Cuevas, Prabhat Ranjan Pujahari, Alessandra Cappati, Alexander Belyaev, Florian Bury, James Buchanan, Roman Kogler, Andrea Giammanco, Marco Toliman Lucchini, Guenther Dissertori, Francesca Cavallari, José María Hernández Calama, Antonello Pellecchia, Efe Yazgan, Nils Faltermann, Yuri Gershtein, Sinan Sagir, Tomas Lindén, Halil Saka, Luca Cadamuro, Florencia Canelli, Simone Pigazzini, Armando Bermudez Martinez, Dmitri Konstantinov, Ksenia Shchelina, Cesar Augusto Bernardes, Bingran Wang, Qiang Li, Nicolò Trevisani, Tapio Lampén, Md Naimuddin, Barry Blumenfeld, Leonid Levchuk, Claudio Grandi, Giovanni Petrucciani, Dayong Wang, Marco Zanetti, Cristina Botta, Danilo Meuser, Martti Raidal, John Conway, Jaime Leon Holgado, Paolo Giacomelli, Jay R. Dittmann, Yalcin Guler, Agni Bethani, Marcin Konecki, Franco Ligabue, Alexander Grohsjean, Lourdes Urda, Mahmoud Moussa Abdelkhalek Gadallah, Silvano Tosi, Martina Malberti, Merve Ince Lezki, Jochen Schieck, Leonardo Cristella, Ernesto Migliore, Pritam Kalbhor, Silvia Goy Lopez, Ashish Sharma, Tommaso Diotalevi, Nikolaos Manthos, Lisa Benato, Suman Chatterjee, Émilien Chapon, JUAN ALCARAZ MAESTRE, Antonio Vilela Pereira, Álvaro Navarro-Tobar, Thong Q. Nguyen, Zhenbin Wu, Maria Clemencia Mora Herrera, Zhengyun You, Agostino De Iorio, Ilaria Vai, Gilvan Alves, Sandeep Bhowmik, Cristina Fernández Bedoya, Nabin Poudyal, Markus Seidel, Andre Sznajder, Ali Eren Simsek, Tamer Elkafrawy, Pedro Galli Mercadante, Kenyi Hurtado Anampa, Luca Giommi, Efe Yigitbasi, Andrea Massironi, Andrey Starodumov, Jose Ruiz, Mario Pelliccioni, Caroline Collard, Alexei Safonov, WILLIAM FORD, Junghwan Goh, Spandan Mondal, Jingyan Li, German Ruben Martinez, Walter Snoeys, Evgueni Tcherniaev, Matteo Presilla, Stephen Mrenna, Jeremy Andrea, Panja Luukka, Saranya Samik Ghosh, Rogelio Reyes-Almanza, Joachim Mnich, Sandor Lokos, Darin Acosta, Karl Ehatäht, Aurelijus Rinkevicius, Frank Geurts, Isabel Josa Mutuberria, Junquan Tao, Paul Kyberd, Ece ASILAR, David D'Enterria, Sergey Polikarpov, Daniel Savoiu, Adish Vartak, Francesco Fienga, Jay Lawhorn, Arabella Martelli, Robert Cousins, Santeri Laurila, Jorma Tuominiemi, Andrey Popov, Jehad Mousa, Martin Grunewald, Paolo Spagnolo, Nicholas Wardle, Redwan Habibullah, Robert Klanner, Frank Golf, Isidro González Caballero, Crisostomo Sciacca, Oscar Gonzalez Lopez, Tahys Janssen, Jeremi Niedziela, Robert Bainbridge, Elizabeth Starling, Andrea Rizzi, Javier Alberto Murillo Quijada, Klaus Rabbertz, Luigi (Gigi) Rolandi, Federica Legger, Andrew Ivanov, ANKITA MEHTA, Ioannis Papadopoulos, Greg Landsberg, Malte Backhaus, Aliakbar Ebrahimi, INSEOK YOON, Sara Fiorendi, ANDREA PICCINELLI, Dmitry Kirpichnikov, Jennifer Ngadiuba, Tamas Almos Vami, Ivan Heredia de la Cruz, Maciej Malawski, Vuko Brigljević, Thomas McCauley, Vittorio Raoul Tavolaro, Pablo Martinez Ruiz del Arbol, Davide Fiorina, Kaur Sandeep, Reddy Pratap Gandrajula, Luca Malgeri, Leszek Grzanka, Peter Elmer, Lea Caminada, Kenneth Osterberg, Emil Sørensen Bols, Leandar Litov, Lata Panwar, Zhicai Zhang, Anton Stepennov, Arnd Meyer, Tatyana Dimova, Christophe Ochando, Alberto Ruiz Jimeno, J B Singh, Johannes Lange, Peter Wittich, Maria Cruz Fouz Iglesias, Korbinian Schweiger, Gaetano Marco Dallavalle, Pietro Faccioli, Rafael Eduardo Sosa Ricardo, Avi Yagil, Muhammad Gul, Jaana Heikkilä, Arne Christoph Reimers, Michele Arneodo, José Flix Molina, Javier Fernandez Menendez, Alexander Tapper, Valeria D'Amante, Sandra S. Padula, George Alverson, Lev Dudko, Juan Pablo Fernández Ramos, Karl Ecklund, Martin Delcourt, Salvatore Costa, Yacine Haddad, Paolo Meridiani, Ignacio Redondo, Marco Monteno, Gautier Hamel de Monchenault, Salvatore Rappoccio, Gerrit Van Onsem, Bora Akgun, Thomas Reis, Anna Colaleo, Marco CUFFIANI, Torben Lange, Lutz Feld, Varun Sharma, Gabriella Pásztor, Nicolas Stylianou, Sung-Won Lee, Joel Goldstein, Daniel Diaz, Paolo Azzurri, Oleg Filatov, Welathantri Dharmaratna, Benedikt Vormwald, Davide Zuolo, Ram Krishna Sharma, Ian Watson, Javier Mauricio Duarte, Vilius Cepaitis, Andreas Hinzmann, Nikkie Deelen, Matthias Kasemann, Manfred Paulini, Paolo Dini, Andre Frankenthal, Kevin Lannon, Mithat Kaya, Myriam Schönenberger, Florian Beaudette, Barbara Alvarez Gonzalez, Nuno Leonardo, Maxim Titov, Laurent Forthomme, Jose Enrique Palencia Cortezon, Rainer Wallny, Pietro Vischia, Schoefbeck Robert, Thea Aarrestad, Pieter David, Liuyao Zhang, Tae Jeong Kim, Marco Pieri, Sunil Manohar Dogra, Shabnam Jabeen, Guido Emilio Tonelli, Mar Capeans, Davide Di Croce, Ugur Kiminsu, J.F. Benitez, Luiz Mundim, Jason Lee, Jorgen D'Hondt, Maria Cepeda, Pallabi Das, Ksenia De Leo, Deborah Pinna, Morgan Lethuillier, Soureek Mitra, Bruno Lenzi, Sergio Novaes, Antonio Delgado Peris, Amina Zghiche, Pieter Everaerts, Gurpreet Singh Chahal, Hannu Siikonen, Mohammed Attia Mahmoud, André David Tinoco Mendes, Olga Evdokimov, Pierluigi Bortignon, Shubhanshu Chauhan, Simone Gennai, Freya Blekman, Furkan Dolek, Federica Maria Simone, Raffaele Gerosa, Benjamin Krikler, Geoffrey Hall, Eija Tuominen, Marko Dragicevic, Antonio Perez-Calero Yzquierdo, Nadezda Chernyavskaya, Mykhailo Dalchenko, Joona Juhani Havukainen, Biagio Rossi, Ibrahim Soner Zorbakir, Sandra Consuegra Rodriguez, Roberto Covarelli, Chiara Amendola, Christophorus Grab, Mojtaba Mohammadi Najafabadi, Henning Flaecher, Dilson De Jesus Damiao, Arthur Moraes, Lucas Taylor, Graham Wilson, Rui Xiao, Minsuk Kim, Alberto Sanchez-Hernandez, Tobias Robert Jakob Kramer, Marino Missiroli, Jan-Frederik Schulte, Fotios Ptochos, Shudhashil Bharthuar, Justin Williams, Helen Heath, Wolfgang Waltenberger, Henning Kirschenmann, Hannes Jung, Emrah Tiras, Camilo Carrillo Montoya, Alberto Zucchetta, Ralf Ulrich, Calandri Alessandro, Tahereh Sadat Niknejad, Guillelmo Gomez-Ceballos, Felipe Araujo, Kadri Ozdemir, Patrizia Azzi, Muhammad Alibordi, Vladimir Gavrilov, Johannes Haller, Kati Lassila-Perini, Abhijith Gandrakota, Konstantinos Theofilatos, Gouranga Kole, Eliza Melo da Costa, Andrea Davide Benaglia, Sebastian Wuchterl, Jesus Puerta Pelayo, Laura Martikainen, Ram Krishna Dewanjee, Christophe Delaere, Simon Regnard, Aaron Dominguez, Emanuele Usai, Matthew Herndon, Kenichi Hatakeyama, LUCA GUZZI, Alberto Belloni, Harrison Bertrand Prosper, Federico Siviero, Mariana Shopova, Mauro Donega, Abideh Jafari, Antonio Cassese, Federico De Guio, UTTIYA SARKAR, Aashaq Shah, Oliver Gutsche, Claudio Caputo, Mauro Emanuele Dinardo, Elisabetta Manca, Amedeo Staiano, Soumya Mukherjee, Thiago Rafael Fernandez Perez Tomei, Sudhir Malik, Clemens Lange, and Bożena Boimska
Subjects: General Physics and Astronomy
Published: 2022

36. Metformin and breast cancer: an opportunity for pharmacogenetics

Author: Elisabet Cuyàs, Begoña Martin-Castillo, and Javier A. Menendez
Subjects: Aging, Diabetes Mellitus, Type 2, Pharmacogenetics, Receptor, ErbB-2, Humans, Hypoglycemic Agents, Breast Neoplasms, Female, Cell Biology, Metformin
Published: 2022

37. Measurement of the production cross section for Z+b jets in proton-proton collisions at s=13 TeV

Author: Mikko Voutilainen, Stefaan Tavernier, Jordan Nash, Dmitry Kondratyev, Francisco Garcia, Raghunath Pradhan, Gabriella Pugliese, Alberto Escalante del Valle, Praveen Chandra Tiwari, Mate Csanad, Kadir Saygin, Kenneth Bloom, Pietro Govoni, Maximilian Pérez Prada, Arie Bodek, Riccardo Salvatico, Mikhail Dubinin, Andrea Cardini, Chang-Seong Moon, Ted Kolberg, Guenakh Mitselmakher, Kun Shi, Caglar Zorbilmez, Lorenzo Viliani, Ankush Reddy Kanuganti, Wesley Smith, Mikael Myllymäki, Hesham El Faham, Walaa Elmetenawee, Erhan Gülmez, Giovanni Abbiendi, Fabrizio Palla, Valentina Sola, Matthias Schröder, Cristina Riccardi, Sami Lehti, Abanti Ranadhir Sahasransu, Joseph Reichert, Jussi Viinikainen, Badder Marzocchi, Luke Kreczko, Hugues Lattaud, FLAVIA CETORELLI, Georgios Konstantinos Krintiras, Samet Lezki, Stefano Belforte, Maria Savina, Reza Goldouzian, Márton Bartók, Daniele Fasanella, Erika Garutti, Louis Moureaux, Nadia Pastrone, Danyer Pérez Adán, Muhammad Ahmad, Konstantin Androsov, Toni Sculac, Arun Kumar, Andreas Pfeiffer, Jorge Berenguer Antequera, Giuseppe Della Ricca, Eduard De La Cruz Burelo, Joern Schwandt, Christopher Tully, Luigi Calligaris, Wael HAJ AHMAD (Vael HAJAHMAD), Jennifer Ott, Francisco Javier Cuevas Maestro, Steffen Albrecht, Pablo Matorras-Cuevas, Prabhat Ranjan Pujahari, Alessandra Cappati, Alexander Belyaev, Florian Bury, Roman Kogler, Andrea Giammanco, Marco Toliman Lucchini, Guenther Dissertori, Francesca Cavallari, José María Hernández Calama, Efe Yazgan, Nils Faltermann, Yuri Gershtein, Sinan Sagir, Tomas Lindén, Halil Saka, Luca Cadamuro, Florencia Canelli, Simone Pigazzini, Armando Bermudez Martinez, Dmitri Konstantinov, Ksenia Shchelina, Cesar Augusto Bernardes, Bingran Wang, Qiang Li, Richard Breedon, Nicolò Trevisani, Tapio Lampén, Md Naimuddin, Barry Blumenfeld, Leonid Levchuk, Claudio Grandi, Giovanni Petrucciani, Dayong Wang, Marco Zanetti, Cristina Botta, Danilo Meuser, Martti Raidal, John Conway, Jaime Leon Holgado, Paolo Giacomelli, Jay R. Dittmann, Yalcin Guler, Agni Bethani, Marcin Konecki, Franco Ligabue, Alexander Grohsjean, Lourdes Urda, Mahmoud Moussa Abdelkhalek Gadallah, Silvano Tosi, Martina Malberti, Merve Ince Lezki, Jochen Schieck, Leonardo Cristella, Ernesto Migliore, Pritam Kalbhor, Silvia Goy Lopez, Ashish Sharma, Tommaso Diotalevi, Nikolaos Manthos, Lisa Benato, Suman Chatterjee, Émilien Chapon, JUAN ALCARAZ MAESTRE, Antonio Vilela Pereira, Álvaro Navarro-Tobar, Thong Q. Nguyen, Zhenbin Wu, Maria Clemencia Mora Herrera, Zhengyun You, Agostino De Iorio, Ilaria Vai, Gilvan Alves, Sandeep Bhowmik, Cristina Fernández Bedoya, Nabin Poudyal, Markus Seidel, Andre Sznajder, Ali Eren Simsek, Tamer Elkafrawy, Pedro Galli Mercadante, Kenyi Hurtado Anampa, Luca Giommi, Efe Yigitbasi, Andrea Massironi, Andrey Starodumov, Jose Ruiz, Mario Pelliccioni, Caroline Collard, Alexei Safonov, WILLIAM FORD, Junghwan Goh, Spandan Mondal, Jingyan Li, German Ruben Martinez, Walter Snoeys, Evgueni Tcherniaev, Matteo Presilla, Stephen Mrenna, Jeremy Andrea, Panja Luukka, Saranya Samik Ghosh, Rogelio Reyes-Almanza, Joachim Mnich, Sandor Lokos, Fonseca de Souza Sandro, Darin Acosta, Karl Ehatäht, Aurelijus Rinkevicius, Frank Geurts, Isabel Josa Mutuberria, Junquan Tao, Paul Kyberd, Ece ASILAR, David D'Enterria, Sergey Polikarpov, Daniel Savoiu, Adish Vartak, Francesco Fienga, Jay Lawhorn, Arabella Martelli, Robert Cousins, Santeri Laurila, Jorma Tuominiemi, Andrey Popov, Jehad Mousa, Martin Grunewald, Tirso Alejandro Gomez Espinosa, Paolo Spagnolo, Nicholas Wardle, Redwan Habibullah, Robert Klanner, Frank Golf, Isidro González Caballero, Crisostomo Sciacca, Oscar Gonzalez Lopez, Tahys Janssen, Jeremi Niedziela, Robert Bainbridge, Elizabeth Starling, Andrea Rizzi, Javier Alberto Murillo Quijada, Klaus Rabbertz, Luigi (Gigi) Rolandi, Federica Legger, Andrew Ivanov, ANKITA MEHTA, Ioannis Papadopoulos, Greg Landsberg, Malte Backhaus, Aliakbar Ebrahimi, INSEOK YOON, Sara Fiorendi, ANDREA PICCINELLI, Dmitry Kirpichnikov, Arsen Khvedelidze, Jennifer Ngadiuba, Tamas Almos Vami, Ivan Heredia de la Cruz, Maciej Malawski, Vuko Brigljević, Thomas McCauley, Vittorio Raoul Tavolaro, Pablo Martinez Ruiz del Arbol, Davide Fiorina, Kaur Sandeep, Reddy Pratap Gandrajula, Luca Malgeri, Leszek Grzanka, Peter Elmer, Lea Caminada, Kenneth Osterberg, Emil Sørensen Bols, Leandar Litov, Lata Panwar, Zhicai Zhang, Anton Stepennov, Arnd Meyer, Tatyana Dimova, Christophe Ochando, Gabriel Ramirez Sanchez, Alberto Ruiz Jimeno, J B Singh, Johannes Lange, Peter Wittich, Maria Cruz Fouz Iglesias, Korbinian Schweiger, Gaetano Marco Dallavalle, Pietro Faccioli, Rafael Eduardo Sosa Ricardo, Avi Yagil, Muhammad Gul, Jaana Heikkilä, Arne Christoph Reimers, Michele Arneodo, José Flix Molina, Javier Fernandez Menendez, Alexander Tapper, Valeria D'Amante, Sandra S. Padula, George Alverson, Lev Dudko, Juan Pablo Fernández Ramos, Karl Ecklund, Martin Delcourt, Salvatore Costa, Yacine Haddad, Carlos Eugenio Perez Lara, Paolo Meridiani, Ignacio Redondo, Marco Monteno, Gautier Hamel de Monchenault, Salvatore Rappoccio, Gerrit Van Onsem, Thomas Reis, Anna Colaleo, Marco CUFFIANI, Torben Lange, Lutz Feld, Varun Sharma, Gabriella Pásztor, Nicolas Stylianou, Sung-Won Lee, Joel Goldstein, Daniel Diaz, Paolo Azzurri, Oleg Filatov, Sergio Lo Meo, Welathantri Dharmaratna, ÜMİT SÖZBİLİR, Davide Zuolo, Ram Krishna Sharma, Ian Watson, Javier Mauricio Duarte, Vilius Cepaitis, Andreas Hinzmann, Nikkie Deelen, Matthias Kasemann, Manfred Paulini, Paolo Dini, Andre Frankenthal, Kevin Lannon, Mithat Kaya, Florian Beaudette, Barbara Alvarez Gonzalez, Nuno Leonardo, Maxim Titov, Laurent Forthomme, Jose Enrique Palencia Cortezon, Rainer Wallny, Pietro Vischia, Schoefbeck Robert, Thea Aarrestad, Kevin Mota Amarilo, Gaia Grosso, Pieter David, Liuyao Zhang, Tae Jeong Kim, Marco Pieri, Sunil Manohar Dogra, Shabnam Jabeen, Guido Emilio Tonelli, Mar Capeans, Davide Di Croce, Upul Sonnadara, Ugur Kiminsu, J.F. Benitez, Luiz Mundim, Jason Lee, Jorgen D'Hondt, Maria Cepeda, Pallabi Das, Ksenia De Leo, Deborah Pinna, Morgan Lethuillier, Soureek Mitra, Bruno Lenzi, Sergio Novaes, Antonio Delgado Peris, Amina Zghiche, Pieter Everaerts, Gurpreet Singh Chahal, Hannu Siikonen, Mohammed Attia Mahmoud, André David Tinoco Mendes, Olga Evdokimov, Pierluigi Bortignon, Shubhanshu Chauhan, Carlos Perez Dengra, Simone Gennai, Freya Blekman, Furkan Dolek, Umberto Dosselli, Federica Maria Simone, Raffaele Gerosa, Benjamin Krikler, Geoffrey Hall, Eija Tuominen, Marko Dragicevic, Antonio Perez-Calero Yzquierdo, Nadezda Chernyavskaya, Mykhailo Dalchenko, Joona Juhani Havukainen, Biagio Rossi, Ibrahim Soner Zorbakir, Pavel Parygin, Sandra Consuegra Rodriguez, Roberto Covarelli, Chiara Amendola, Christophorus Grab, Mojtaba Mohammadi Najafabadi, Henning Flaecher, Dilson De Jesus Damiao, Arthur Moraes, Lucas Taylor, Graham Wilson, Rui Xiao, Minsuk Kim, Francisco Matorras, Alberto Sanchez-Hernandez, Tobias Robert Jakob Kramer, Marino Missiroli, Jan-Frederik Schulte, Fotios Ptochos, Shudhashil Bharthuar, Justin Williams, Helen Heath, Wolfgang Waltenberger, Henning Kirschenmann, Hannes Jung, Emrah Tiras, Camilo Carrillo Montoya, Yu Zhang, Alberto Zucchetta, Ralf Ulrich, Calandri Alessandro, Tahereh Sadat Niknejad, Guillelmo Gomez-Ceballos, Felipe Araujo, Kadri Ozdemir, Patrizia Azzi, Muhammad Alibordi, Vladimir Gavrilov, Johannes Haller, Kati Lassila-Perini, Abhijith Gandrakota, Konstantinos Theofilatos, Gouranga Kole, Eliza Melo da Costa, Andrea Davide Benaglia, Sebastian Wuchterl, Jesus Puerta Pelayo, Laura Martikainen, Ram Krishna Dewanjee, Christophe Delaere, Simon Regnard, Aaron Dominguez, Emanuele Usai, Matthew Herndon, Kenichi Hatakeyama, LUCA GUZZI, Alberto Belloni, Harrison Bertrand Prosper, Federico Siviero, Mariana Shopova, Mauro Donega, Abideh Jafari, Antonio Cassese, Federico De Guio, UTTIYA SARKAR, Aashaq Shah, Oliver Gutsche, Claudio Caputo, Mauro Emanuele Dinardo, Elisabetta Manca, Amedeo Staiano, Soumya Mukherjee, Thiago Rafael Fernandez Perez Tomei, Sudhir Malik, Clemens Lange, and Bożena Boimska
Published: 2022

38. Virgin Olive Oil and Health: Summary of the III International Conference on Virgin Olive Oil and Health Consensus Report, JAEN (Spain) 2018

Author: José J. Gaforio, Francesco Visioli, Catalina Alarcón-de-la-Lastra, Olga Castañer, Miguel Delgado-Rodríguez, Monserrat Fitó, Antonio F. Hernández, Jesús R. Huertas, Miguel A. Martínez-González, Javier A. Menendez, Jesús de la Osada, Angeliki Papadaki, Tesifón Parrón, Jorge E. Pereira, María A. Rosillo, Cristina Sánchez-Quesada, Lukas Schwingshackl, Estefanía Toledo, and Aristidis M. Tsatsakis
Subjects: olive oil, polyphenols, hydroxytyrosol, Mediterranean diet, cardiovascular disease, cancer, neurodegeneration, sustainable diet, sustainable agriculture, Nutrition. Foods and food supply, TX341-641
Abstract: The Mediterranean diet is considered as the foremost dietary regimen and its adoption is associated with the prevention of degenerative diseases and an extended longevity. The preeminent features of the Mediterranean diet have been agreed upon and the consumption of olive oil stands out as the most peculiar one. Indeed, the use of olive oil as the nearly exclusive dietary fat is what mostly characterizes the Mediterranean area. Plenty of epidemiological studies have correlated that the consumption of olive oil was associated with better overall health. Indeed, extra virgin olive oil contains (poly)phenolic compounds that are being actively investigated for their purported biological and pharma-nutritional properties. On 18 and 19 May 2018, several experts convened in Jaen (Spain) to discuss the most recent research on the benefits of olive oil and its components. We reported a summary of that meeting (reviewing several topics related to olive oil, not limited to health) and concluded that substantial evidence is accruing to support the widespread opinion that extra virgin olive oil should, indeed, be the fat of choice when it comes to human health and sustainable agronomy.
Published: 2019
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39. Extra Virgin Olive Oil Contains a Phenolic Inhibitor of the Histone Demethylase LSD1/KDM1A

Author: Elisabet Cuyàs, Juan Gumuzio, Jesús Lozano-Sánchez, David Carreras, Sara Verdura, Laura Llorach-Parés, Melchor Sanchez-Martinez, Elisabet Selga, Guillermo J. Pérez, Fabiana S. Scornik, Ramon Brugada, Joaquim Bosch-Barrera, Antonio Segura-Carretero, Ángel G. Martin, José Antonio Encinar, and Javier A. Menendez
Subjects: phenolics, secoiridoids, cancer, cancer stem cells, SOX2, metabolism, neurological disorders, Nutrition. Foods and food supply, TX341-641
Abstract: The lysine-specific histone demethylase 1A (LSD1) also known as lysine (K)-specific demethylase 1A (KDM1A) is a central epigenetic regulator of metabolic reprogramming in obesity-associated diseases, neurological disorders, and cancer. Here, we evaluated the ability of oleacein, a biophenol secoiridoid naturally present in extra virgin olive oil (EVOO), to target LSD1. Molecular docking and dynamic simulation approaches revealed that oleacein could target the binding site of the LSD1 cofactor flavin adenosine dinucleotide with high affinity and at low concentrations. At higher concentrations, oleacein was predicted to target the interaction of LSD1 with histone H3 and the LSD1 co-repressor (RCOR1/CoREST), likely disturbing the anchorage of LSD1 to chromatin. AlphaScreen-based in vitro assays confirmed the ability of oleacein to act as a direct inhibitor of recombinant LSD1, with an IC50 as low as 2.5 μmol/L. Further, oleacein fully suppressed the expression of the transcription factor SOX2 (SEX determining Region Y-box 2) in cancer stem-like and induced pluripotent stem (iPS) cells, which specifically occurs under the control of an LSD1-targeted distal enhancer. Conversely, oleacein failed to modify ectopic SOX2 overexpression driven by a constitutive promoter. Overall, our findings provide the first evidence that EVOO contains a naturally occurring phenolic inhibitor of LSD1, and support the use of oleacein as a template to design new secoiridoid-based LSD1 inhibitors.
Published: 2019
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40. Intestinal Permeability Study of Clinically Relevant Formulations of Silibinin in Caco-2 Cell Monolayers

Author: Almudena Pérez-Sánchez, Elisabet Cuyàs, Verónica Ruiz-Torres, Luz Agulló-Chazarra, Sara Verdura, Isabel González-Álvarez, Marival Bermejo, Jorge Joven, Vicente Micol, Joaquim Bosch-Barrera, and Javier A. Menendez
Subjects: silibinin, cancer, bioavailability, blood–brain barrier, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: An ever-growing number of preclinical studies have investigated the tumoricidal activity of the milk thistle flavonolignan silibinin. The clinical value of silibinin as a bona fide anti-cancer therapy, however, remains uncertain with respect to its bioavailability and blood–brain barrier (BBB) permeability. To shed some light on the absorption and bioavailability of silibinin, we utilized the Caco-2 cell monolayer model of human intestinal absorption to evaluate the permeation properties of three different formulations of silibinin: silibinin-meglumine, a water-soluble form of silibinin complexed with the amino-sugar meglumine; silibinin-phosphatidylcholine, the phytolipid delivery system Siliphos; and Eurosil85/Euromed, a milk thistle extract that is the active component of the nutraceutical Legasil with enhanced bioavailability. Our approach predicted differential mechanisms of transport and blood–brain barrier permeabilities between the silibinin formulations tested. Our assessment might provide valuable information about an idoneous silibinin formulation capable of reaching target cancer tissues and accounting for the observed clinical effects of silibinin, including a recently reported meaningful central nervous system activity against brain metastases.
Published: 2019
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41. The Data Quality Monitoring Software for the CMS experiment at the LHC: past, present and future

Author: Azzolini Virginia, Broen van Besien, Bugelskis Dmitrijus, Hreus Tomas, Maeshima Kaori, Javier Fernandez Menendez, Norkus Antanas, James Fraser Patrick, Rovere Marco, and Andre Schneider Marcel
Subjects: Physics, QC1-999
Abstract: The Data Quality Monitoring software is a central tool in the CMS experiment. It is used in the following key environments: (i) Online, for real-time detector monitoring; (ii) Offline, for the prompt-offline-feedback and final fine-grained data quality analysis and certification; (iii) Validation of all the reconstruction software production releases; (iv) Validation in Monte Carlo productions. Though the basic structure of the Run1 DQM system remains the same for Run2, between the Run1 and Run2 periods, the DQM system underwent substantial upgrades in many areas, not only to adapt to the surrounding infrastructure changes, but also to provide improvements to meet the growing needs of the collaboration with an emphasis on more sophisticated methods for evaluating data quality. We need to cope with the higher-energy and -luminosity proton-proton collision data, as well as the data from various special runs, such as Heavy Ion runs. In this contribution, we will describe the current DQM software, structure and workflow in the different environments. We then discuss the performance and our experiences with the DQM system in Run2. The main technical challenges which we have encountered and the solutions adopted during Run2 will also be discussed, including efficient use of memory in multithreading environments. Finally, we present the prospect of a future DQM upgrade with emphasis on functionality and long-term robustness for LHC Run3.
Published: 2019
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42. Progesterone receptor isoform-dependent cross-talk between prolactin and fatty acid synthase in breast cancer

Author: Adriana Papadimitropoulou, Sara Verdura, Ruth Lupu, Luciano Vellon, Javier A. Menendez, Travis Vander Steen, Elisabet Cuyàs, Wen Y. Chen, and Susan K Peirce
Subjects: Aging, purl.org/becyt/ford/1 [https], luminal breast cancer, 4-Butyrolactone, Estrogen -- Receptors, Databases, Genetic, Gene expression, Protein Isoforms, Promoter Regions, Genetic, biology, Chemistry, Carcinoma, Ductal, Breast, Up-Regulation, Fatty Acid Synthase, Type I, Fatty acid synthase, LUMINAL BREAST CANCER, Receptors, Progesterone, Mama -- Càncer -- Aspectes endocrins, hormones, hormone substitutes, and hormone antagonists, Research Paper, Gene isoform, endocrine system, medicine.medical_specialty, prolactin receptor, Receptors, Prolactin, Breast Neoplasms, Mama -- Càncer -- Tractament, Estrògens -- Receptors, Cell Line, Tumor, G129R, Internal medicine, Progesterone receptor, medicine, Humans, Secretion, RNA, Messenger, purl.org/becyt/ford/1.6 [https], ENDOCRINE THERAPY, Breast -- Cancer -- Treatment, Interleukin-6, endocrine therapy, Prolactin receptor, Receptor Cross-Talk, Cell Biology, PROLACTIN RECEPTOR, Prolactin, Endocrinology, Cell culture, Breast -- Cancer -- Endocrine aspects, biology.protein
Abstract: Progesterone receptor (PR) isoforms can drive unique phenotypes in luminal breast cancer (BC). Here, we hypothesized that PR-B and PR-A isoforms differentially modify the cross-talk between prolactin and fatty acid synthase (FASN) in BC. We profiled the responsiveness of the FASN gene promoter to prolactin in T47Dco BC cells constitutively expressing PR-A and PR-B, in the PR-null variant T47D-Y cell line, and in PR-null T47D-Y cells engineered to stably re-express PR-A (T47D-YA) or PR-B (T47D-YB). The capacity of prolactin to up-regulate FASN gene promoter activity in T47Dco cells was lost in T47D-Y and TD47-YA cells. Constitutively up-regulated FASN gene expression in T47-YB cells and its further stimulation by prolactin were both suppressed by the prolactin receptor antagonist hPRL-G129R. The ability of the FASN inhibitor C75 to decrease prolactin secretion was more conspicuous in T47-YB cells. In T47D-Y cells, which secreted notably less prolactin and downregulated prolactin receptor expression relative to T47Dco cells, FASN blockade resulted in an augmented secretion of prolactin and up-regulation of prolactin receptor expression. Our data reveal unforeseen PR-B isoform-specific regulatory actions in the cross-talk between prolactin and FASN signaling in BC. These findings might provide new PR-B/FASN-centered predictive and therapeutic modalities in luminal intrinsic BC subtypes Fil: Menendez, Javier A.. Institut Català d'Oncologia; España. Institut d’Investigació Biomèdica de Girona; España Fil: Peirce, Susan K.. Clemson University. Pearce Center Professional Communication; Estados Unidos Fil: Papadimitropoulou, Adriana. Biomedical Research Foundation Academy of Athens; Grecia Fil: Cuyàs, Elisabet. Institut Català d'Oncologia; España. Institut d’Investigació Biomèdica de Girona; España Fil: Steen, Travis Vander. Mayo Foundation for Medical Education and Research. Mayo Clinic; Estados Unidos Fil: Verdura, Sara. Institut Català d'Oncologia; España. Institut d’Investigació Biomèdica de Girona; España Fil: Vellón, Luciano. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Chen, Wen Y.. Clemson University; Estados Unidos Fil: Lupu, Ruth. Mayo Foundation for Medical Education and Research. Mayo Clinic; Estados Unidos. Clemson University; Estados Unidos. Mayo Clinic Cancer Center; Estados Unidos
Published: 2020

43. Precision measurement of the W boson decay branching fractions in proton-proton collisions at s=13 TeV

Author: Mikko Voutilainen, Stefaan Tavernier, Jordan Nash, Francisco Garcia, Raghunath Pradhan, Gabriella Pugliese, Alberto Escalante del Valle, Praveen Chandra Tiwari, Mate Csanad, Kadir Saygin, Kenneth Bloom, Pietro Govoni, Maximilian Pérez Prada, Arie Bodek, Riccardo Salvatico, Mikhail Dubinin, Andrea Cardini, Chang-Seong Moon, Ted Kolberg, Guenakh Mitselmakher, Kun Shi, Caglar Zorbilmez, Lorenzo Viliani, Ankush Reddy Kanuganti, Wesley Smith, Mikael Myllymäki, Hesham El Faham, Walaa Elmetenawee, Erhan Gülmez, Giovanni Abbiendi, Fabrizio Palla, Valentina Sola, Matthias Schröder, Cristina Riccardi, Sami Lehti, Abanti Ranadhir Sahasransu, Joseph Reichert, Jussi Viinikainen, Badder Marzocchi, Luke Kreczko, Hugues Lattaud, FLAVIA CETORELLI, Georgios Konstantinos Krintiras, Samet Lezki, Stefano Belforte, Maria Savina, Reza Goldouzian, Márton Bartók, Daniele Fasanella, Erika Garutti, Louis Moureaux, Nadia Pastrone, Danyer Pérez Adán, Muhammad Ahmad, Konstantin Androsov, Toni Sculac, Arun Kumar, Andreas Pfeiffer, Jorge Berenguer Antequera, Giuseppe Della Ricca, Eduard De La Cruz Burelo, Joern Schwandt, Christopher Tully, Luigi Calligaris, Wael HAJ AHMAD (Vael HAJAHMAD), Jennifer Ott, Francisco Javier Cuevas Maestro, Steffen Albrecht, Pablo Matorras-Cuevas, Prabhat Ranjan Pujahari, Alessandra Cappati, Alexander Belyaev, Florian Bury, James Buchanan, Roman Kogler, Andrea Giammanco, Marco Toliman Lucchini, Guenther Dissertori, Francesca Cavallari, José María Hernández Calama, Antonello Pellecchia, Efe Yazgan, Nils Faltermann, Yuri Gershtein, Sinan Sagir, Tomas Lindén, Halil Saka, Luca Cadamuro, Florencia Canelli, Simone Pigazzini, Armando Bermudez Martinez, Dmitri Konstantinov, Ksenia Shchelina, Cesar Augusto Bernardes, Bingran Wang, Qiang Li, Nicolò Trevisani, Tapio Lampén, Md Naimuddin, Barry Blumenfeld, Leonid Levchuk, Claudio Grandi, Giovanni Petrucciani, Dayong Wang, Marco Zanetti, Cristina Botta, Danilo Meuser, Martti Raidal, John Conway, Jaime Leon Holgado, Paolo Giacomelli, Jay R. Dittmann, Yalcin Guler, Agni Bethani, Marcin Konecki, Franco Ligabue, Alexander Grohsjean, Lourdes Urda, Mahmoud Moussa Abdelkhalek Gadallah, Silvano Tosi, Martina Malberti, Merve Ince Lezki, Jochen Schieck, Leonardo Cristella, Ernesto Migliore, Pritam Kalbhor, Silvia Goy Lopez, Ashish Sharma, Tommaso Diotalevi, Nikolaos Manthos, Lisa Benato, Suman Chatterjee, Émilien Chapon, Stéphane PERRIES, JUAN ALCARAZ MAESTRE, Antonio Vilela Pereira, Álvaro Navarro-Tobar, Thong Q. Nguyen, Zhenbin Wu, Maria Clemencia Mora Herrera, Zhengyun You, Agostino De Iorio, Ilaria Vai, Gilvan Alves, Sandeep Bhowmik, Cristina Fernández Bedoya, Nabin Poudyal, Markus Seidel, Andre Sznajder, Ali Eren Simsek, Tamer Elkafrawy, Pedro Galli Mercadante, Kenyi Hurtado Anampa, Luca Giommi, Efe Yigitbasi, Andrea Massironi, Andrey Starodumov, Jose Ruiz, Mario Pelliccioni, Caroline Collard, Alexei Safonov, WILLIAM FORD, Junghwan Goh, Spandan Mondal, Jingyan Li, German Ruben Martinez, Walter Snoeys, Evgueni Tcherniaev, Matteo Presilla, Stephen Mrenna, Jeremy Andrea, Panja Luukka, Saranya Samik Ghosh, Rogelio Reyes-Almanza, Joachim Mnich, Sandor Lokos, Darin Acosta, Karl Ehatäht, Aurelijus Rinkevicius, Frank Geurts, Isabel Josa Mutuberria, Junquan Tao, Paul Kyberd, Ece ASILAR, David D'Enterria, Daniel Savoiu, Adish Vartak, Francesco Fienga, Jay Lawhorn, Arabella Martelli, Robert Cousins, Santeri Laurila, Jorma Tuominiemi, Andrey Popov, Jehad Mousa, Martin Grunewald, Tirso Alejandro Gomez Espinosa, Paolo Spagnolo, Nicholas Wardle, Redwan Habibullah, Robert Klanner, Frank Golf, Isidro González Caballero, Crisostomo Sciacca, Oscar Gonzalez Lopez, Tahys Janssen, Jeremi Niedziela, Robert Bainbridge, Elizabeth Starling, Andrea Rizzi, Javier Alberto Murillo Quijada, Klaus Rabbertz, Luigi (Gigi) Rolandi, Federica Legger, Andrew Ivanov, ANKITA MEHTA, Ioannis Papadopoulos, Greg Landsberg, Malte Backhaus, Aliakbar Ebrahimi, INSEOK YOON, Sara Fiorendi, ANDREA PICCINELLI, Dmitry Kirpichnikov, Jennifer Ngadiuba, Tamas Almos Vami, Ivan Heredia de la Cruz, Maciej Malawski, Vuko Brigljević, Thomas McCauley, Vittorio Raoul Tavolaro, Pablo Martinez Ruiz del Arbol, Davide Fiorina, Kaur Sandeep, Reddy Pratap Gandrajula, Luca Malgeri, Leszek Grzanka, Peter Elmer, Lea Caminada, Kenneth Osterberg, Emil Sørensen Bols, Leandar Litov, Lata Panwar, Zhicai Zhang, Anton Stepennov, Arnd Meyer, Tatyana Dimova, Christophe Ochando, Gabriel Ramirez Sanchez, Alberto Ruiz Jimeno, J B Singh, Johannes Lange, Peter Wittich, Maria Cruz Fouz Iglesias, Korbinian Schweiger, Gaetano Marco Dallavalle, Pietro Faccioli, Rafael Eduardo Sosa Ricardo, Avi Yagil, Muhammad Gul, Jaana Heikkilä, Arne Christoph Reimers, Michele Arneodo, José Flix Molina, Javier Fernandez Menendez, Alexander Tapper, Valeria D'Amante, Sandra S. Padula, George Alverson, Lev Dudko, Juan Pablo Fernández Ramos, Karl Ecklund, Martin Delcourt, Salvatore Costa, Yacine Haddad, Paolo Meridiani, Ignacio Redondo, Marco Monteno, Gautier Hamel de Monchenault, Salvatore Rappoccio, Gerrit Van Onsem, Bora Akgun, Thomas Reis, Anna Colaleo, Marco CUFFIANI, Torben Lange, Lutz Feld, Varun Sharma, Gabriella Pásztor, Nicolas Stylianou, Sung-Won Lee, Joel Goldstein, Daniel Diaz, Paolo Azzurri, Oleg Filatov, Welathantri Dharmaratna, Benedikt Vormwald, Davide Zuolo, Ram Krishna Sharma, Ian Watson, Javier Mauricio Duarte, Vilius Cepaitis, Andreas Hinzmann, Nikkie Deelen, Matthias Kasemann, Manfred Paulini, Paolo Dini, Andre Frankenthal, Kevin Lannon, Mithat Kaya, Myriam Schönenberger, Florian Beaudette, Barbara Alvarez Gonzalez, Nuno Leonardo, Maxim Titov, Laurent Forthomme, Jose Enrique Palencia Cortezon, Rainer Wallny, Pietro Vischia, Schoefbeck Robert, Thea Aarrestad, Pieter David, Liuyao Zhang, Tae Jeong Kim, Marco Pieri, Sunil Manohar Dogra, Shabnam Jabeen, Guido Emilio Tonelli, Mar Capeans, Davide Di Croce, Ugur Kiminsu, J.F. Benitez, Luiz Mundim, Jason Lee, Jorgen D'Hondt, Maria Cepeda, Pallabi Das, Ksenia De Leo, Deborah Pinna, Morgan Lethuillier, Soureek Mitra, Bruno Lenzi, Sergio Novaes, Antonio Delgado Peris, Amina Zghiche, Pieter Everaerts, Gurpreet Singh Chahal, Hannu Siikonen, Mohammed Attia Mahmoud, André David Tinoco Mendes, Olga Evdokimov, Pierluigi Bortignon, Shubhanshu Chauhan, Simone Gennai, Ahmad Lotfy Abdelfattah Ahmad, Freya Blekman, Furkan Dolek, Federica Maria Simone, Raffaele Gerosa, Benjamin Krikler, Geoffrey Hall, Eija Tuominen, Marko Dragicevic, Antonio Perez-Calero Yzquierdo, Nadezda Chernyavskaya, Viola Sordini, Mykhailo Dalchenko, Joona Juhani Havukainen, Biagio Rossi, Ibrahim Soner Zorbakir, Pavel Parygin, Sandra Consuegra Rodriguez, Roberto Covarelli, Chiara Amendola, Christophorus Grab, Mojtaba Mohammadi Najafabadi, Henning Flaecher, Dilson De Jesus Damiao, Arthur Moraes, Lucas Taylor, Graham Wilson, Rui Xiao, Minsuk Kim, Francisco Matorras, Alberto Sanchez-Hernandez, Tobias Robert Jakob Kramer, Marino Missiroli, Jan-Frederik Schulte, Fotios Ptochos, Shudhashil Bharthuar, Justin Williams, Helen Heath, Wolfgang Waltenberger, Henning Kirschenmann, Hannes Jung, Emrah Tiras, Camilo Carrillo Montoya, Alberto Zucchetta, Ralf Ulrich, Calandri Alessandro, Tahereh Sadat Niknejad, Guillelmo Gomez-Ceballos, Felipe Araujo, Kadri Ozdemir, Patrizia Azzi, Muhammad Alibordi, Vladimir Gavrilov, Johannes Haller, Kati Lassila-Perini, Abhijith Gandrakota, Konstantinos Theofilatos, Gouranga Kole, Eliza Melo da Costa, Andrea Davide Benaglia, Sebastian Wuchterl, Jesus Puerta Pelayo, Laura Martikainen, Ram Krishna Dewanjee, Christophe Delaere, Simon Regnard, Aaron Dominguez, Emanuele Usai, Matthew Herndon, Kenichi Hatakeyama, LUCA GUZZI, Alberto Belloni, Harrison Bertrand Prosper, Federico Siviero, Mariana Shopova, Mauro Donega, Abideh Jafari, Antonio Cassese, Federico De Guio, UTTIYA SARKAR, Aashaq Shah, Oliver Gutsche, Claudio Caputo, Mauro Emanuele Dinardo, Elisabetta Manca, Amedeo Staiano, Soumya Mukherjee, Thiago Rafael Fernandez Perez Tomei, Sudhir Malik, Clemens Lange, and Bożena Boimska
Published: 2022

44. Familial chylomicronemia syndrome: The first case reported in Ecuador

Author: Karla Johana Garay García, Ricardo Javier Chong Menendez, Juan Patricio Nogueira, and Jefferson Santiago Piedra Andrade
Subjects: Male, Adult, Hypertriglyceridemia, Lipoprotein Lipase, General Engineering, General Earth and Planetary Sciences, Humans, Hyperlipoproteinemia Type I, Ecuador, General Environmental Science
Abstract: Familial chylomicronemia syndrome (FCS) is a genetic entity with autosomal recessive inheritance. Mutations in genes (such as APOC2, APOAV, LMF-1, GPIHBP-1) that code for proteins that regulate the maturation, transport, or polymerization of lipoprotein lipase-1 are the most common causes, but not the only ones. The objective of this study was to report the first documented case in Ecuador. CLINICAL CASE: A 38-year-old man presented with chronic hepatosplenomegaly, thrombocytopenia, pancreatic atrophy, and severe hypertriglyceridemia refractory to treatment. A molecular analysis was performed by next generation sequencing that determined a deficiency of Lipoprotein Lipase OMIM #238600 in homozygosis. Genetic confirmation is necessary in order to establish the etiology of HTGS for an adequate management of this pathology.
Published: 2022

45. Search for heavy resonances decaying to WW , WZ , or WH boson pairs in a final state consisting of a lepton and a large-radius jet in proton-proton collisions at s=13 TeV

Author: Viacheslav Bunichev, Mikko Voutilainen, Stefaan Tavernier, Jordan Nash, Francisco Garcia, Raghunath Pradhan, Gabriella Pugliese, Altan Cakir, Alberto Escalante del Valle, Mate Csanad, Kadir Saygin, Kenneth Bloom, Pietro Govoni, Maximilian Pérez Prada, Arie Bodek, Mikhail Dubinin, Valentina Mariani, Chang-Seong Moon, Ted Kolberg, Guenakh Mitselmakher, Diana Seitova, Kun Shi, Dhanush Anil Hangal, Caglar Zorbilmez, Lorenzo Viliani, Ankush Reddy Kanuganti, Wesley Smith, Mikael Myllymäki, Hesham El Faham, Walaa Elmetenawee, Erhan Gülmez, Giovanni Abbiendi, Fabrizio Palla, Valentina Sola, Matthias Schröder, Cristina Riccardi, Sami Lehti, Abanti Ranadhir Sahasransu, Jussi Viinikainen, Badder Marzocchi, Luke Kreczko, FLAVIA CETORELLI, Georgios Konstantinos Krintiras, Samet Lezki, Stefano Belforte, Maria Savina, Márton Bartók, Daniele Fasanella, Erika Garutti, Nadia Pastrone, Konstantin Androsov, Andreas Pfeiffer, Giuseppe Della Ricca, Eduard De La Cruz Burelo, Lucia Silvestris, Joern Schwandt, Christopher Tully, Luigi Calligaris, Wael HAJ AHMAD (Vael HAJAHMAD), Diego Ciangottini, Jennifer Ott, Francisco Javier Cuevas Maestro, Prabhat Ranjan Pujahari, Alessandra Cappati, Alexander Belyaev, Andrea Giammanco, Marco Toliman Lucchini, Guenther Dissertori, Francesca Cavallari, José María Hernández Calama, Efe Yazgan, Nils Faltermann, Yuri Gershtein, Sinan Sagir, Tomas Lindén, Halil Saka, Luca Cadamuro, Florencia Canelli, Simone Pigazzini, Armando Bermudez Martinez, Cesar Augusto Bernardes, Qiang Li, Nicolò Trevisani, Tapio Lampén, Md Naimuddin, Barry Blumenfeld, Gustavo Gil Da Silveira, Leonid Levchuk, Claudio Grandi, Giovanni Petrucciani, Dayong Wang, Marco Zanetti, Cristina Botta, Danilo Meuser, Martti Raidal, John Conway, Paolo Giacomelli, Agni Bethani, Marcin Konecki, Franco Ligabue, Alexander Grohsjean, Silvano Tosi, Martina Malberti, Merve Ince Lezki, Jochen Schieck, Leonardo Cristella, Ernesto Migliore, Tommaso Diotalevi, Nikolaos Manthos, Lisa Benato, Salvatore Buontempo, Émilien Chapon, Stéphane PERRIES, JUAN ALCARAZ MAESTRE, Antonio Vilela Pereira, Thong Q. Nguyen, Zhenbin Wu, Maria Clemencia Mora Herrera, Zhengyun You, Agostino De Iorio, Ilaria Vai, Gilvan Alves, Sandeep Bhowmik, Cristina Fernández Bedoya, Nabin Poudyal, Markus Seidel, Andre Sznajder, Ali Eren Simsek, Tamer Elkafrawy, Pedro Galli Mercadante, Kenyi Hurtado Anampa, Luca Giommi, Andrea Massironi, Jose Ruiz, Mario Pelliccioni, Caroline Collard, Alexei Safonov, WILLIAM FORD, Junghwan Goh, Spandan Mondal, German Ruben Martinez, Walter Snoeys, Evgueni Tcherniaev, Stephen Mrenna, Jeremy Andrea, Panja Luukka, Ashraf Mohamed, Saranya Samik Ghosh, Chiara Aimè, Joachim Mnich, Fonseca de Souza Sandro, Karl Ehatäht, Aurelijus Rinkevicius, Frank Geurts, Isabel Josa Mutuberria, Junquan Tao, Paul Kyberd, Ece ASILAR, David D'Enterria, Adish Vartak, Francesco Fienga, Jay Lawhorn, Mapse Barroso Ferreira, Arabella Martelli, Robert Cousins, Santeri Laurila, Jorma Tuominiemi, Andrey Popov, Stefano Ragazzi, Jehad Mousa, Martin Grunewald, Tirso Alejandro Gomez Espinosa, Paolo Spagnolo, Nicholas Wardle, Redwan Habibullah, Robert Klanner, Frank Golf, Isidro González Caballero, Crisostomo Sciacca, Oscar Gonzalez Lopez, Tahys Janssen, Jeremi Niedziela, Robert Bainbridge, Elizabeth Starling, Andrea Rizzi, Javier Alberto Murillo Quijada, Klaus Rabbertz, Luigi (Gigi) Rolandi, Federica Legger, Andrew Ivanov, ANKITA MEHTA, Ioannis Papadopoulos, Greg Landsberg, Malte Backhaus, Aliakbar Ebrahimi, INSEOK YOON, Sara Fiorendi, Jennifer Ngadiuba, Tamas Almos Vami, Ivan Heredia de la Cruz, Andrea Venturi, Maciej Malawski, Vuko Brigljević, Thomas McCauley, Vittorio Raoul Tavolaro, Pablo Martinez Ruiz del Arbol, Ulascan Sarica, Reddy Pratap Gandrajula, Luca Malgeri, Francesco Moscatelli, Leszek Grzanka, Peter Elmer, Lea Caminada, Kenneth Osterberg, Emil Sørensen Bols, Leandar Litov, Zhicai Zhang, Anton Stepennov, Arnd Meyer, Tatyana Dimova, Gabriel Ramirez Sanchez, Alberto Ruiz Jimeno, Johannes Lange, Peter Wittich, Maria Cruz Fouz Iglesias, Ivan Vila, Korbinian Schweiger, Gaetano Marco Dallavalle, Pietro Faccioli, Rafael Eduardo Sosa Ricardo, Avi Yagil, Muhammad Gul, Jaana Heikkilä, Arne Christoph Reimers, Michele Arneodo, José Flix Molina, Javier Fernandez Menendez, Alexander Tapper, Sandra S. Padula, George Alverson, Lev Dudko, Juan Pablo Fernández Ramos, Karl Ecklund, Martin Delcourt, Salvatore Costa, Yacine Haddad, Paolo Meridiani, Ignacio Redondo, Marco Monteno, Gautier Hamel de Monchenault, Salvatore Rappoccio, Gerrit Van Onsem, Thomas Reis, Anna Colaleo, Marco CUFFIANI, Lutz Feld, Varun Sharma, Gabriella Pásztor, Sung-Won Lee, Joel Goldstein, Paolo Azzurri, Sergio Lo Meo, Welathantri Dharmaratna, Benedikt Vormwald, Davide Zuolo, Ram Krishna Sharma, Ian Watson, Javier Mauricio Duarte, Andreas Hinzmann, Matthias Kasemann, Manfred Paulini, Paolo Dini, Andre Frankenthal, Kevin Lannon, Mithat Kaya, Myriam Schönenberger, Florian Beaudette, Barbara Alvarez Gonzalez, Nuno Leonardo, Maxim Titov, Laurent Forthomme, Jose Enrique Palencia Cortezon, Rainer Wallny, Pietro Vischia, Schoefbeck Robert, Kevin Mota Amarilo, Pieter David, Liuyao Zhang, Tae Jeong Kim, Marco Pieri, Sunil Manohar Dogra, Shabnam Jabeen, Guido Emilio Tonelli, Davide Di Croce, Upul Sonnadara, Ugur Kiminsu, J.F. Benitez, Luiz Mundim, Jason Lee, Jorgen D'Hondt, Maria Cepeda, Deborah Pinna, Morgan Lethuillier, Soureek Mitra, Sergio Novaes, Antonio Delgado Peris, Amina Zghiche, Pieter Everaerts, Hannu Siikonen, Mohammed Attia Mahmoud, André David Tinoco Mendes, Olga Evdokimov, Pierluigi Bortignon, Shubhanshu Chauhan, Simone Gennai, Ahmad Lotfy Abdelfattah Ahmad, Freya Blekman, Umberto Dosselli, Federica Maria Simone, Raffaele Gerosa, Benjamin Krikler, Geoffrey Hall, Eija Tuominen, Marko Dragicevic, Antonio Perez-Calero Yzquierdo, Viola Sordini, Mykhailo Dalchenko, Joona Juhani Havukainen, Biagio Rossi, Ibrahim Soner Zorbakir, Pavel Parygin, Sandra Consuegra Rodriguez, Roberto Covarelli, Chiara Amendola, Christophorus Grab, Mojtaba Mohammadi Najafabadi, Henning Flaecher, Dilson De Jesus Damiao, Arthur Moraes, Lucas Taylor, Graham Wilson, Minsuk Kim, Francisco Matorras, Alberto Sanchez-Hernandez, Tobias Robert Jakob Kramer, Marino Missiroli, Jan-Frederik Schulte, Fotios Ptochos, Shudhashil Bharthuar, Helen Heath, Wolfgang Waltenberger, Henning Kirschenmann, Alberto Zucchetta, Ralf Ulrich, Calandri Alessandro, Guillelmo Gomez-Ceballos, Kadri Ozdemir, Patrizia Azzi, Nikola Godinovic, Muhammad Alibordi, Vladimir Gavrilov, Johannes Haller, Gouranga Kole, Eliza Melo da Costa, Andrea Davide Benaglia, Jesus Puerta Pelayo, Laura Martikainen, Ram Krishna Dewanjee, Christophe Delaere, Simon Regnard, Aaron Dominguez, Emanuele Usai, Matthew Herndon, Alberto Belloni, Harrison Bertrand Prosper, Federico Siviero, Mariana Shopova, Mauro Donega, Abideh Jafari, Antonio Cassese, Federico De Guio, Aashaq Shah, Oliver Gutsche, Claudio Caputo, Mauro Emanuele Dinardo, Elisabetta Manca, Amedeo Staiano, Thiago Rafael Fernandez Perez Tomei, Sudhir Malik, Clemens Lange, and Bożena Boimska
Published: 2022

46. Measurement of the Inclusive and Differential Higgs Boson Production Cross Sections in the Decay Mode to a Pair of τ Leptons in pp Collisions at s=13 TeV

Author: Viacheslav Bunichev, Mikko Voutilainen, Stefaan Tavernier, Jordan Nash, Francisco Garcia, Raghunath Pradhan, Gabriella Pugliese, Altan Cakir, Alberto Escalante del Valle, Mate Csanad, Kadir Saygin, Kenneth Bloom, Pietro Govoni, Maximilian Pérez Prada, Arie Bodek, Mikhail Dubinin, Valentina Mariani, Chang-Seong Moon, Ted Kolberg, Guenakh Mitselmakher, Diana Seitova, Kun Shi, Dhanush Anil Hangal, Caglar Zorbilmez, Lorenzo Viliani, Ankush Reddy Kanuganti, Wesley Smith, Mikael Myllymäki, Hesham El Faham, Walaa Elmetenawee, Erhan Gülmez, Giovanni Abbiendi, Fabrizio Palla, Valentina Sola, Matthias Schröder, Cristina Riccardi, Sami Lehti, Abanti Ranadhir Sahasransu, Jussi Viinikainen, Badder Marzocchi, Luke Kreczko, Sebastian Brommer, FLAVIA CETORELLI, Georgios Konstantinos Krintiras, Samet Lezki, Stefano Belforte, Maria Savina, Márton Bartók, Daniele Fasanella, Erika Garutti, Shalini Thakur, Nadia Pastrone, Konstantin Androsov, Andreas Pfeiffer, Giuseppe Della Ricca, Eduard De La Cruz Burelo, Lucia Silvestris, Joern Schwandt, Christopher Tully, Luigi Calligaris, Wael HAJ AHMAD (Vael HAJAHMAD), Diego Ciangottini, Jennifer Ott, Francisco Javier Cuevas Maestro, Prabhat Ranjan Pujahari, Alessandra Cappati, Alexander Belyaev, Andrea Giammanco, Marco Toliman Lucchini, Guenther Dissertori, Francesca Cavallari, José María Hernández Calama, Efe Yazgan, Nils Faltermann, Yuri Gershtein, Sinan Sagir, Tomas Lindén, Halil Saka, Luca Cadamuro, Florencia Canelli, Simone Pigazzini, Armando Bermudez Martinez, Cesar Augusto Bernardes, Qiang Li, Nicolò Trevisani, Tapio Lampén, Md Naimuddin, Barry Blumenfeld, Gustavo Gil Da Silveira, Leonid Levchuk, Claudio Grandi, Giovanni Petrucciani, Dayong Wang, Marco Zanetti, Cristina Botta, Danilo Meuser, Martti Raidal, John Conway, Paolo Giacomelli, Agni Bethani, Marcin Konecki, Franco Ligabue, Alexander Grohsjean, Silvano Tosi, Martina Malberti, Merve Ince Lezki, Jochen Schieck, Leonardo Cristella, Ernesto Migliore, Tommaso Diotalevi, Nikolaos Manthos, Lisa Benato, Salvatore Buontempo, Émilien Chapon, Stéphane PERRIES, JUAN ALCARAZ MAESTRE, Antonio Vilela Pereira, Thong Q. Nguyen, Zhenbin Wu, Maria Clemencia Mora Herrera, Zhengyun You, Agostino De Iorio, Ilaria Vai, Gilvan Alves, Sandeep Bhowmik, Cristina Fernández Bedoya, Nabin Poudyal, Markus Seidel, Andre Sznajder, Ali Eren Simsek, Tamer Elkafrawy, Pedro Galli Mercadante, Kenyi Hurtado Anampa, Luca Giommi, Andrea Massironi, Jose Ruiz, Mario Pelliccioni, Caroline Collard, Alexei Safonov, WILLIAM FORD, Junghwan Goh, Spandan Mondal, German Ruben Martinez, Walter Snoeys, Evgueni Tcherniaev, Stephen Mrenna, Jeremy Andrea, Panja Luukka, Ashraf Mohamed, Saranya Samik Ghosh, Chiara Aimè, Joachim Mnich, Fonseca de Souza Sandro, Karl Ehatäht, Aurelijus Rinkevicius, Frank Geurts, Isabel Josa Mutuberria, Junquan Tao, Paul Kyberd, Ece ASILAR, David D'Enterria, Sergey Polikarpov, Adish Vartak, Francesco Fienga, Jay Lawhorn, Mapse Barroso Ferreira, Arabella Martelli, Robert Cousins, Santeri Laurila, Jorma Tuominiemi, Andrey Popov, Stefano Ragazzi, Jehad Mousa, Martin Grunewald, Tirso Alejandro Gomez Espinosa, Paolo Spagnolo, Nicholas Wardle, Redwan Habibullah, Robert Klanner, Frank Golf, Isidro González Caballero, Crisostomo Sciacca, Oscar Gonzalez Lopez, Tahys Janssen, Jeremi Niedziela, Robert Bainbridge, Elizabeth Starling, Andrea Rizzi, Javier Alberto Murillo Quijada, Klaus Rabbertz, Luigi (Gigi) Rolandi, Federica Legger, Andrew Ivanov, ANKITA MEHTA, Ioannis Papadopoulos, Greg Landsberg, Malte Backhaus, Aliakbar Ebrahimi, INSEOK YOON, Sara Fiorendi, Jennifer Ngadiuba, Tamas Almos Vami, Ivan Heredia de la Cruz, Andrea Venturi, Maciej Malawski, Vuko Brigljević, Thomas McCauley, Vittorio Raoul Tavolaro, Pablo Martinez Ruiz del Arbol, Ulascan Sarica, Reddy Pratap Gandrajula, Luca Malgeri, Francesco Moscatelli, Leszek Grzanka, Peter Elmer, Lea Caminada, Kenneth Osterberg, Emil Sørensen Bols, Leandar Litov, Zhicai Zhang, Anton Stepennov, Arnd Meyer, Tatyana Dimova, Gabriel Ramirez Sanchez, Alberto Ruiz Jimeno, Johannes Lange, Peter Wittich, Maria Cruz Fouz Iglesias, Ivan Vila, Patrizia Barria, Korbinian Schweiger, Gaetano Marco Dallavalle, Pietro Faccioli, Rafael Eduardo Sosa Ricardo, Avi Yagil, Muhammad Gul, Jaana Heikkilä, Arne Christoph Reimers, Michele Arneodo, José Flix Molina, Javier Fernandez Menendez, Alexander Tapper, Sandra S. Padula, George Alverson, Lev Dudko, Juan Pablo Fernández Ramos, Karl Ecklund, Martin Delcourt, Salvatore Costa, Yacine Haddad, Paolo Meridiani, Ignacio Redondo, Marco Monteno, Gautier Hamel de Monchenault, Salvatore Rappoccio, Gerrit Van Onsem, Thomas Reis, Anna Colaleo, Marco CUFFIANI, Lutz Feld, Varun Sharma, Gabriella Pásztor, Sung-Won Lee, Joel Goldstein, Paolo Azzurri, Welathantri Dharmaratna, Davide Zuolo, Ram Krishna Sharma, Ian Watson, Javier Mauricio Duarte, Andreas Hinzmann, Matthias Kasemann, Manfred Paulini, Paolo Dini, Andre Frankenthal, Kevin Lannon, Mithat Kaya, Florian Beaudette, Barbara Alvarez Gonzalez, Nuno Leonardo, Maxim Titov, Laurent Forthomme, Jose Enrique Palencia Cortezon, Rainer Wallny, Pietro Vischia, Schoefbeck Robert, Sheng Luo, Kevin Mota Amarilo, Gaia Grosso, Pieter David, Liuyao Zhang, Tae Jeong Kim, Marco Pieri, Alain Albert, Sunil Manohar Dogra, Shabnam Jabeen, Guido Emilio Tonelli, Davide Di Croce, Upul Sonnadara, Ugur Kiminsu, J.F. Benitez, Luiz Mundim, Jason Lee, Jorgen D'Hondt, Maria Cepeda, Deborah Pinna, Morgan Lethuillier, Soureek Mitra, Sergio Novaes, Antonio Delgado Peris, Amina Zghiche, Pieter Everaerts, Hannu Siikonen, Mohammed Attia Mahmoud, André David Tinoco Mendes, Olga Evdokimov, Pierluigi Bortignon, Shubhanshu Chauhan, Carlos Perez Dengra, Simone Gennai, Ahmad Lotfy Abdelfattah Ahmad, Freya Blekman, Umberto Dosselli, Federica Maria Simone, Raffaele Gerosa, Benjamin Krikler, Geoffrey Hall, Eija Tuominen, Marko Dragicevic, Antonio Perez-Calero Yzquierdo, Viola Sordini, Mykhailo Dalchenko, Joona Juhani Havukainen, Biagio Rossi, Ibrahim Soner Zorbakir, Pavel Parygin, Sandra Consuegra Rodriguez, Roberto Covarelli, Chiara Amendola, Christophorus Grab, Mojtaba Mohammadi Najafabadi, Henning Flaecher, Dilson De Jesus Damiao, Arthur Moraes, Lucas Taylor, Graham Wilson, Minsuk Kim, Francisco Matorras, Alberto Sanchez-Hernandez, Tobias Robert Jakob Kramer, Marino Missiroli, Jan-Frederik Schulte, Fotios Ptochos, Shudhashil Bharthuar, Helen Heath, Wolfgang Waltenberger, Henning Kirschenmann, Alberto Zucchetta, Ralf Ulrich, Calandri Alessandro, Guillelmo Gomez-Ceballos, Kadri Ozdemir, Patrizia Azzi, Nikola Godinovic, Muhammad Alibordi, Vladimir Gavrilov, Johannes Haller, Gouranga Kole, Eliza Melo da Costa, Andrea Davide Benaglia, Jesus Puerta Pelayo, Laura Martikainen, Ram Krishna Dewanjee, Christophe Delaere, Simon Regnard, Aaron Dominguez, Emanuele Usai, Matthew Herndon, Alberto Belloni, Harrison Bertrand Prosper, Federico Siviero, Mariana Shopova, Mauro Donega, Abideh Jafari, Antonio Cassese, Federico De Guio, Aashaq Shah, Oliver Gutsche, Claudio Caputo, Mauro Emanuele Dinardo, Elisabetta Manca, Amedeo Staiano, Thiago Rafael Fernandez Perez Tomei, Sudhir Malik, Clemens Lange, and Bożena Boimska
Subjects: General Physics and Astronomy
Published: 2022

47. Systemic overexpression of C-C motif chemokine ligand 2 promotes metabolic dysregulation and premature death in mice with accelerated aging

Author: Salvador Fernández-Arroyo, Gerard Baiges-Gaya, Anna Hernández-Aguilera, Jordi Camps, Elisabet Rodríguez-Tomàs, Jorge Joven, Javier A. Menendez, Fedra Luciano-Mateo, Meritxell Arenas, and Noemí Cabré
Subjects: Male, Aging, Chemokine, Longevity, Mitochondrial Dynamics, Proinflammatory cytokine, Animals, Genetically Modified, LMNA, energy metabolism, Autophagy, medicine, Animals, Muscle, Skeletal, Cellular Senescence, Chemokine CCL2, PI3K/AKT/mTOR pathway, Tissue homeostasis, Progeria, biology, C-C motif chemokine ligand 2, progeria, Cell Biology, DNA Methylation, Lamin Type A, one-carbon metabolism, medicine.disease, Mice, Mutant Strains, Mitochondria, Muscle, Up-Regulation, Cell biology, Mice, Inbred C57BL, Disease Models, Animal, Mutation, DNA methylation, biology.protein, Signal Transduction, Research Paper
Abstract: Injection of tissues with senescent cells induces changes that mimic aging, and this process is delayed in mice engineered to eliminate senescent cells, which secrete proinflammatory cytokines, including C-C motif chemokine ligand 2 (Ccl2). Circulating levels of Ccl2 correlate with age, but the impact of Ccl2 on tissue homeostasis has not been established. We generated an experimental model by crossbreeding mice overexpressing Ccl2 with progeroid mice bearing a mutation in the lamin A (Lmna) gene. Wild-type animals and progeroid mice that do not overexpress Ccl2 were used as controls. Ccl2 overexpression decreased the lifespan of the progeroid mice and induced the dysregulation of glycolysis, the citric acid cycle and one-carbon metabolism in skeletal muscle, driving dynamic changes in energy metabolism and DNA methylation. This impact on cellular bioenergetics was associated with mitochondrial alterations and affected cellular metabolism, autophagy and protein synthesis through AMPK/mTOR pathways. The data revealed the ability of Ccl2 to promote death in mice with accelerated aging, which supports its putative use as a biomarker of an increased senescent cell burden and for the assessment of the efficacy of interventions aimed at extending healthy aging.
Published: 2020

48. Metformin and SARS-CoV-2: mechanistic lessons on air pollution to weather the cytokine/thrombotic storm in COVID-19

Author: Javier A. Menendez
Subjects: Mitochondrial ROS, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), medicine.medical_treatment, air pollution, Pneumonia, Viral, Inflammation, medicine.disease_cause, Proinflammatory cytokine, Betacoronavirus, medicine, Humans, Hypoglycemic Agents, Pandemics, Coronavirus, Aged, particulate matter, business.industry, Interleukin-6, SARS-CoV-2, aging, Drug Repositioning, COVID-19, Thrombosis, Cell Biology, Calcium Release Activated Calcium Channels, Metformin, Thrombotic storm, Cytokine, Immunology, Research Perspective, medicine.symptom, business, Coronavirus Infections, Reactive Oxygen Species, medicine.drug, Signal Transduction
Abstract: Pathological signaling in the lung induced by particulate matter (PM) air pollution partially overlaps with that provoked by COVID-19, the pandemic disease caused by infection with the novel coronavirus SARS-CoV-2. Metformin is capable of suppressing one of the molecular triggers of the proinflammatory and prothrombotic processes of urban PM air pollution, namely the mitochondrial ROS/Ca2+ release-activated Ca2+ channels (CRAC)/IL-6 cascade. Given the linkage between mitochondrial functionality, ion channels, and inflamm-aging, the ability of metformin to target mitochondrial electron transport and prevent ROS/CRAC-mediated IL-6 release might illuminate new therapeutic avenues to quell the raging of the cytokine and thrombotic-like storms that are the leading causes of COVID-19 morbidity and mortality in older people. The incorporation of infection rates, severity and lethality of SARS-CoV-2 infections as new outcomes of metformin usage in elderly populations at risk of developing severe COVID-19, together with the assessment of bronchial/serological titers of inflammatory cytokines and D-dimers, could provide a novel mechanistic basis for the consideration of metformin as a therapeutic strategy against the inflammatory and thrombotic states underlying the gerolavic traits of SARS-CoV-2 infection.
Published: 2020

49. The LSD1 inhibitor iadademstat (ORY-1001) targets SOX2-driven breast cancer stem cells: a potential epigenetic therapy in luminal-B and HER2-positive breast cancer subtypes

Author: Juan Gumuzio, Joaquim Bosch-Barrera, Joan Brunet, Tomás Alarcón, José Antonio Encinar, Elisabet Cuyàs, Sara Verdura, Begoña Martin-Castillo, Angel G. Martin, and Javier A. Menendez
Subjects: cancer stem cells, Aging, Stem cells -- Cancer, Breast Neoplasms, Cèl·lules mare -- Càncer, Epigenesis, Genetic, Càncer de mama, breast cancer, Breast cancer, SOX2, Cancer stem cell, Cell Line, Tumor, Humans, Medicine, Epigenetics, Enzyme Inhibitors, Aged, Histone Demethylases, epigenetics, Cancer stem cells, business.industry, SOXB1 Transcription Factors, reprogramming, Reprogramming, KDM1A, Cell Biology, Middle Aged, Epigenètica, Mama -- Càncer -- Tractament, medicine.disease, Patient-derived xenografts, Breast -- Cancer --Treatment, Neoplastic Stem Cells, Cancer research, Female, patient-derived xenografts, Stem cell, business, Epigenetic therapy, Research Paper
Abstract: Altres ajuts: Fundació Oncolliga Girona, Generalitat Valenciana (PROMETEO/2016/006) SOX2 is a core pluripotency-associated transcription factor causally related to cancer initiation, aggressiveness, and drug resistance by driving the self-renewal and seeding capacity of cancer stem cells (CSC). Here, we tested the ability of the clinically proven inhibitor of the lysine-specific demethylase 1 (LSD1/KDM1A) iadademstat (ORY-100) to target SOX2-driven CSC in breast cancer. Iadademstat blocked CSC-driven mammosphere formation in breast cancer cell lines that are dependent on SOX2 expression to maintain their CSC phenotype. Iadademstat prevented the activation of an LSD1-targeted stemness-specific SOX2 enhancer in CSC-enriched 3-dimensional spheroids. Using high-throughput transcriptional data available from the METABRIC dataset, high expression of SOX2 was significantly more common in luminal-B and HER2-enriched subtypes according to PAM50 classifier and in IntClust1 (high proliferating luminal-B) and IntClust 5 (luminal-B and HER2-amplified) according to integrative clustering. Iadademstat significantly reduced mammospheres formation by CSC-like cells from a multidrug-resistant luminal-B breast cancer patient-derived xenograft but not of those from a treatment-naïve luminal-A patient. Iadademstat reduced the expression of SOX2 in luminal-B but not in luminal-A mammospheres, likely indicating a selective targeting of SOX2-driven CSC. The therapeutic relevance of targeting SOX2-driven breast CSC suggests the potential clinical use of iadademstat as an epigenetic therapy in luminal-B and HER2-positive subtypes.
Published: 2020

50. Evidence for X(3872) in Pb-Pb Collisions and Studies of its Prompt Production at sNN=5.02 TeV

Author: Mikko Voutilainen, Stefaan Tavernier, Jordan Nash, Francisco Garcia, Gabriella Pugliese, Altan Cakir, Alberto Escalante del Valle, Mate Csanad, Kenneth Bloom, Pietro Govoni, Maximilian Pérez Prada, Arie Bodek, Riccardo Di Maria, Valentina Mariani, Chang-Seong Moon, Ted Kolberg, Guenakh Mitselmakher, Lesya Shchutska, Kun Shi, Dhanush Anil Hangal, Caglar Zorbilmez, Lorenzo Viliani, Wesley Smith, Walaa Elmetenawee, Erhan Gülmez, Giovanni Abbiendi, Fabrizio Palla, Kevin Pedro, Valentina Sola, Matthias Schröder, Cristina Riccardi, Johan Borg, Sami Lehti, Jussi Viinikainen, Badder Marzocchi, Luke Kreczko, Georgios Konstantinos Krintiras, Samet Lezki, Stefano Belforte, Márton Bartók, Daniele Fasanella, Erika Garutti, Shalini Thakur, Nadia Pastrone, Heiner Tholen, Konstantin Androsov, Andreas Pfeiffer, Giuseppe Della Ricca, Eduard De La Cruz Burelo, Lucia Silvestris, Joern Schwandt, Christopher Tully, Luigi Calligaris, Wael HAJ AHMAD (Vael HAJAHMAD), Diego Ciangottini, Francisco Javier Cuevas Maestro, Prabhat Ranjan Pujahari, Alessandra Cappati, Alexander Belyaev, Andrea Giammanco, Marco Toliman Lucchini, Guenther Dissertori, Francesca Cavallari, José María Hernández Calama, Efe Yazgan, Nils Faltermann, Yuri Gershtein, Sinan Sagir, Tomas Lindén, Halil Saka, Luca Cadamuro, Florencia Canelli, Simone Pigazzini, Giorgia Miniello, Armando Bermudez Martinez, Manfred Krammer, Cesar Augusto Bernardes, Qiang Li, Nicolò Trevisani, Giacomo Fedi, Tapio Lampén, Md Naimuddin, Barry Blumenfeld, Gustavo Gil Da Silveira, Leonid Levchuk, Claudio Grandi, Giovanni Petrucciani, Dayong Wang, Alessandro Di Mattia, Marco Zanetti, Volodymyr Myronenko, Cristina Botta, Danilo Meuser, Martti Raidal, John Conway, Rostyslav Shevchenko, Paolo Giacomelli, Jay R. Dittmann, Yalcin Guler, Marcin Konecki, Franco Ligabue, Alexander Grohsjean, Silvano Tosi, Martina Malberti, Merve Ince Lezki, Nicolò Tosi, Jochen Schieck, Leonardo Cristella, Ernesto Migliore, Nikolaos Manthos, Lisa Benato, Salvatore Buontempo, Émilien Chapon, Stéphane PERRIES, JUAN ALCARAZ MAESTRE, Nicola Minafra, Antonio Vilela Pereira, Thong Q. Nguyen, Zhenbin Wu, Maria Clemencia Mora Herrera, Agostino De Iorio, Ilaria Vai, Rohan Bhandari, Gilvan Alves, Sandeep Bhowmik, Cristina Fernández Bedoya, Raffaello D'Alessandro, Nabin Poudyal, Markus Seidel, Andre Sznajder, Ali Eren Simsek, Pedro Galli Mercadante, Kenyi Hurtado Anampa, Luca Giommi, Michael Wang, Andrea Massironi, Jose Ruiz, Mario Pelliccioni, Caroline Collard, WILLIAM FORD, Junghwan Goh, Spandan Mondal, German Ruben Martinez, Walter Snoeys, Evgueni Tcherniaev, Stephen Mrenna, Jeremy Andrea, Panja Luukka, Ashraf Mohamed, Saranya Samik Ghosh, Joachim Mnich, Fonseca de Souza Sandro, Karl Ehatäht, Aurelijus Rinkevicius, Frank Geurts, Isabel Josa Mutuberria, Junquan Tao, Paul Kyberd, David D'Enterria, Sergey Polikarpov, Adish Vartak, Francesco Fienga, Jay Lawhorn, Arabella Martelli, Robert Cousins, Eric CONTE, Santeri Laurila, Jorma Tuominiemi, James Keaveney, Andrey Popov, Stefano Ragazzi, Jehad Mousa, Martin Grunewald, Tirso Alejandro Gomez Espinosa, Paolo Spagnolo, Nicholas Wardle, Robert Klanner, Frank Golf, Isidro González Caballero, Crisostomo Sciacca, Oscar Gonzalez Lopez, Tahys Janssen, Jeremi Niedziela, Robert Bainbridge, Elizabeth Starling, Andrea Rizzi, Javier Alberto Murillo Quijada, Klaus Rabbertz, Luigi (Gigi) Rolandi, Federica Legger, Andrew Ivanov, ANKITA MEHTA, Ioannis Papadopoulos, Greg Landsberg, Malte Backhaus, Aliakbar Ebrahimi, INSEOK YOON, Sara Fiorendi, Jennifer Ngadiuba, Francesca Ricci-Tam, Tamas Almos Vami, Ivan Heredia de la Cruz, Andrea Venturi, Cameron Bravo, Vuko Brigljević, Vittorio Raoul Tavolaro, Pablo Martinez Ruiz del Arbol, Ulascan Sarica, Reddy Pratap Gandrajula, Luca Malgeri, Peter Elmer, Lea Caminada, Kenneth Osterberg, Emil Sørensen Bols, Leandar Litov, Zhicai Zhang, Andrea Gozzelino, Anton Stepennov, Arnd Meyer, Tatyana Dimova, Seth Zenz, Alberto Ruiz Jimeno, J B Singh, Johannes Lange, Peter Wittich, Maria Cruz Fouz Iglesias, Ivan Vila, Patrizia Barria, Korbinian Schweiger, Gaetano Marco Dallavalle, Pietro Faccioli, Rafael Eduardo Sosa Ricardo, Jaana Heikkilä, Arne Christoph Reimers, Michele Arneodo, José Flix Molina, Javier Fernandez Menendez, Alexander Tapper, Sandra S. Padula, George Alverson, Juan Pablo Fernández Ramos, Karl Ecklund, Ali Harb, Salvatore Costa, Yacine Haddad, Paolo Meridiani, Ignacio Redondo, Marco Monteno, Gautier Hamel de Monchenault, Salvatore Rappoccio, Gerrit Van Onsem, Thomas Reis, Kunal Kothekar, Anna Colaleo, Marco CUFFIANI, Lutz Feld, Varun Sharma, Gabriella Pásztor, Sung-Won Lee, Joel Goldstein, Paolo Azzurri, Yagya Joshi, Welathantri Dharmaratna, Benedikt Vormwald, Davide Zuolo, Ram Krishna Sharma, Ian Watson, Javier Mauricio Duarte, Andreas Hinzmann, Brent Yates, Matthias Kasemann, Manfred Paulini, Paolo Dini, Andre Frankenthal, Kevin Lannon, Mithat Kaya, Christian Autermann, Myriam Schönenberger, Florian Beaudette, Barbara Alvarez Gonzalez, Nuno Leonardo, Maxim Titov, Laurent Forthomme, Jose Enrique Palencia Cortezon, Rainer Wallny, Pietro Vischia, Schoefbeck Robert, Pieter David, Tae Jeong Kim, Marco Pieri, Alain Albert, Shabnam Jabeen, Guido Emilio Tonelli, Davide Di Croce, Upul Sonnadara, Ugur Kiminsu, J.F. Benitez, Luiz Mundim, Jason Lee, Jorgen D'Hondt, Maria Cepeda, Deborah Pinna, Morgan Lethuillier, Soureek Mitra, Sergio Novaes, Antonio Delgado Peris, Amina Zghiche, Pieter Everaerts, Hannu Siikonen, Mohammed Attia Mahmoud, André David Tinoco Mendes, Olga Evdokimov, Pierluigi Bortignon, Shubhanshu Chauhan, Simone Gennai, Freya Blekman, Furkan Dolek, Sercan Sen, Umberto Dosselli, Federica Maria Simone, Raffaele Gerosa, Benjamin Krikler, Geoffrey Hall, Eija Tuominen, Vincenzo Monaco, Marta Felcini, Daniel Klein, Marko Dragicevic, Giovanni Zevi Della Porta, Antonio Perez-Calero Yzquierdo, Viola Sordini, Mykhailo Dalchenko, Joona Juhani Havukainen, Biagio Rossi, Francesco Luigi Navarria, Ibrahim Soner Zorbakir, Sandra Consuegra Rodriguez, Roberto Covarelli, Chiara Amendola, Christophorus Grab, Mojtaba Mohammadi Najafabadi, Henning Flaecher, Dilson De Jesus Damiao, Arthur Moraes, Lucas Taylor, Graham Wilson, Minsuk Kim, Francisco Matorras, Mara Soares, Ilse Krätschmer, Alberto Sanchez-Hernandez, Marino Missiroli, Jan-Frederik Schulte, Fotios Ptochos, Helen Heath, Wolfgang Waltenberger, Henning Kirschenmann, Alberto Zucchetta, Ralf Ulrich, Calandri Alessandro, Guillelmo Gomez-Ceballos, Kadri Ozdemir, Patrizia Azzi, Nikola Godinovic, Muhammad Alibordi, Vladimir Gavrilov, Johannes Haller, Gouranga Kole, Eliza Melo da Costa, Andrea Davide Benaglia, Vito Palladino, Jesus Puerta Pelayo, Ram Krishna Dewanjee, Christophe Delaere, Simon Regnard, Aaron Dominguez, Emanuele Usai, Matthew Herndon, Alberto Belloni, Harrison Bertrand Prosper, Mariana Shopova, Mauro Donega, Abideh Jafari, Antonio Cassese, Federico De Guio, Aashaq Shah, Oliver Gutsche, Claudio Caputo, Mauro Emanuele Dinardo, PAO-TI CHANG, Emilio Meschi, Elisabetta Manca, Amedeo Staiano, Thiago Rafael Fernandez Perez Tomei, Marta Verweij, Sudhir Malik, Clemens Lange, and Bożena Boimska
Subjects: 010308 nuclear & particles physics, 0103 physical sciences, General Physics and Astronomy, 010306 general physics, 01 natural sciences
Published: 2022

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