188 results on '"Giannino G"'
Search Results
2. Beta-blockers after STEMI: prognostic impact and predictors of adherence, results from the real-world FAST-STEMI registry
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Ravetti, E, primary, Giacobbe, F, additional, Annone, U, additional, Giannino, G, additional, Di Vita, U, additional, Troncone, M, additional, Morena, A, additional, Carmagnola, L, additional, Nebiolo, M, additional, De Filippo, O, additional, Bruno, F, additional, Gaido, L, additional, D'ascenzo, F, additional, Giammaria, M, additional, and De Ferrari, G M, additional
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- 2023
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3. Real world prognostic impact and predictors of adherence to statin therapy after STEMI on first year follow up: results from the FAST STEMI registry
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Morena, A, primary, Giacobbe, F, additional, Annone, U, additional, Ravetti, E, additional, Nebiolo, M, additional, Di Vita, U, additional, Giannino, G, additional, Troncone, M, additional, Carmagnola, L, additional, De Filippo, O, additional, Bruno, F, additional, D'ascenzo, F, additional, Gaido, L, additional, Giammaria, M, additional, and De Ferrari, G M, additional
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- 2023
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4. Anatomic vs ischemia-driven strategies for percutaneous coronary revascularization in chronic coronary syndrome: a network meta-analysis
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Giacobbe, F, primary, Valente, E, additional, Giannino, G, additional, Yip, H C, additional, Di Vita, U, additional, Carmagnola, L, additional, De Filippo, O, additional, Bruno, F, additional, Iannaccone, M, additional, Biondi Zoccai, G, additional, Gasparini, M, additional, Pocock, S, additional, Escaned, J, additional, De Ferrari, G M, additional, and D'ascenzo, F, additional
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- 2023
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5. Real-world impact on mortality of drug adherence to statin, beta-blocker and ACEi/ARB therapy in post-STEMI patients with preserved EF: results from the FAST STEMI registry
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Giannino, G, primary, Giacobbe, F, additional, Annone, U, additional, Ravetti, E, additional, Nebiolo, M, additional, Di Vita, U, additional, Morena, A, additional, Troncone, M, additional, Carmagnola, L, additional, De Filippo, O, additional, Bruno, F, additional, D'ascenzo, F, additional, Gaido, L, additional, Giammaria, M, additional, and De Ferrari, G M, additional
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- 2023
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6. High-Q asymmetrically cladded silicon nitride 1D photonic crystals cavities and hybrid external cavity lasers for sensing in air and liquids (vol 11, pg 4183, 2022)
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Iadanza, S, Mendoza-Castro, Jh, Oliveira, T, Butler, Sm, Tedesco, A, Giannino, G, Lendl, B, Grande, M, and O'Faolain, L
- Published
- 2022
7. CLINICAL AND GENETIC FEATURES OF JUVENILE ONSET LONE ATRIAL FIBRILLATION
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Bertello, E, Berruquier, P, Dusi, V, Saglietto, A, Vallino, C, Tallone, L, Solano, A, Giannino, G, Vairo, A, Angelini, F, Del Prever, G Brach, Pidello, S, Raineri, C, Giustetto, C, Matta, M, Castagno, D, Ferraris, F, Deaglio, S, De Ferrari, G, and Anselmino, M
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- 2024
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8. REAL WORLD USAGE OF RANOLAZINE FOR ANTIARRHYTHMIC PURPOSES: SINGLE CENTER EXPERIENCE
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Braia, V, Manai, R, Bocchino, P, Angelini, F, Gallone, G, De Lio, G, Pidello, S, Saglietto, A, Boretto, P, Marcelli, G, Melis, D, Giannino, G, Gravinese, C, Frea, S, Raineri, C, De Ferrari, G, and Dusi, V
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- 2024
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9. CONTINUOUS LEFT STELLATE GANGLION BLOCK DURING VT ABLATION TO SLOW VT AND IMPROVE ABLATION OUTCOME
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Morena, A, Matta, M, Ferraris, F, Frea, S, Anselmino, M, Berruquier, P, Gravinese, C, Giannino, G, Angelini, F, Saglietto, A, De Ferrari, G, and Dusi, V
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- 2024
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10. Optimization of Silicon-Nitride-Based Nanowires in Nonlinear Mach-Zehnder Interferometers
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Giannino, G., primary, Tedesco, A., additional, D'Orazio, A., additional, O'Faolain, L., additional, and Grande, M., additional
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- 2018
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11. Thermally Stable External Cavity Laser Based on Silicon Nitride Periodic Nanostructures
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Iadanza, S., primary, Bakoz, A., additional, Panettieri, D., additional, Tedesco, A., additional, Giannino, G., additional, Grande, M., additional, and OrFaolain, L., additional
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- 2018
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12. High-Q asymmetrically cladded silicon nitride 1D photonic crystals cavities and hybrid external cavity lasers for sensing in air and liquids
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Iadanza Simone, Mendoza-Castro Jesus Hernan, Oliveira Taynara, Butler Sharon M., Tedesco Alessio, Giannino Giuseppe, Lendl Bernhard, Grande Marco, and O’Faolain Liam
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integrated sensors ,laser ,nanophotonics ,photonic crystals ,refractive index sensing ,silicon photonics ,Physics ,QC1-999 - Abstract
In this paper we show a novel design of high Q-factor silicon nitride (SiN) 1D photonic crystal (PhC) cavities side-coupled to curved waveguides, operating with both silica and air cladding. The engineering of the etched 1D PhC cavity sidewalls angle allows for high Q-factors over a wide range of upper cladding compositions, and the achievement of the highest calculated Q-factor for non-suspended asymmetric SiN PhC structures. We show the employment of these type of SiN PhC cavities in hybrid external cavity laser (HECL) configuration, with mode-hop free single mode laser operation over a broad range of injected currents (from 25 mA to 65 mA), milliwatts of power output (up to 9 mW) and side-mode suppression ratios in the range of 40 dB. We demonstrate the operation of these devices as compact and energy efficient optical sensors that respond to refractive index changes in the surrounding medium the measurement of sodium chloride (from 0% to 25%) and sucrose (from 0% to 25%) in aqueous solution. In HECL configuration, the RI sensor exhibits a 2 orders of magnitude improvement in detection limit compared to the passive microcavity. We also discuss the possibility for applying these devices as novel transducers for refractive index changes that are induced by analyte specific absorption of infrared radiation by the target analytes present in gas or liquid phase.
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- 2022
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13. Cardiovascular autonomic function tests in migraine patients
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DE MARINIS, Milena, D'Arcangelo, S, Petrelli, A, and Giannino, G.
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- 2007
14. Trattamento della trombosi venosa distale in pazienti deambulanti
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Manganaro, Agatino, Lembo, D, Parisi, R, Buda, D, Giannino, D, Giannino, G., and Consolo, F.
- Published
- 2001
15. Farrera de Pallars. Nueva Sede del Centre Art I Natura
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Fracchia, BEATRICE MARIA, Garnero, C, Giannino, G, and Gigli, D.
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- 1998
16. Erratum to: High-Q asymmetrically cladded silicon nitride 1D photonic crystals cavities and hybrid external cavity lasers for sensing in air and liquids
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Iadanza Simone, Mendoza-Castro Jesus Hernan, Oliveira Taynara, Butler Sharon M., Tedesco Alessio, Giannino Giuseppe, Lendl Bernhard, Grande Marco, and O’Faolain Liam
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Physics ,QC1-999 - Published
- 2022
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17. Evolution of translational control and the emergence of genes and open reading frames in human and non-human primate hearts.
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Ruiz-Orera J, Miller DC, Greiner J, Genehr C, Grammatikaki A, Blachut S, Mbebi J, Patone G, Myronova A, Adami E, Dewani N, Liang N, Hummel O, Muecke MB, Hildebrandt TB, Fritsch G, Schrade L, Zimmermann WH, Kondova I, Diecke S, van Heesch S, and Hübner N
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- Animals, Humans, Species Specificity, Transcriptome, Gene Expression Profiling methods, Induced Pluripotent Stem Cells metabolism, Ribosomes metabolism, Ribosomes genetics, Primates genetics, Cells, Cultured, Open Reading Frames genetics, Protein Biosynthesis genetics, Evolution, Molecular, Myocytes, Cardiac metabolism
- Abstract
Evolutionary innovations can be driven by changes in the rates of RNA translation and the emergence of new genes and small open reading frames (sORFs). In this study, we characterized the transcriptional and translational landscape of the hearts of four primate and two rodent species through integrative ribosome and transcriptomic profiling, including adult left ventricle tissues and induced pluripotent stem cell-derived cardiomyocyte cell cultures. We show here that the translational efficiencies of subunits of the mitochondrial oxidative phosphorylation chain complexes IV and V evolved rapidly across mammalian evolution. Moreover, we discovered hundreds of species-specific and lineage-specific genomic innovations that emerged during primate evolution in the heart, including 551 genes, 504 sORFs and 76 evolutionarily conserved genes displaying human-specific cardiac-enriched expression. Overall, our work describes the evolutionary processes and mechanisms that have shaped cardiac transcription and translation in recent primate evolution and sheds light on how these can contribute to cardiac development and disease., (© 2024. The Author(s).)
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- 2024
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18. Amplification of autoimmune organ damage by NKp46-activated ILC1s.
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Biniaris-Georgallis SI, Aschman T, Stergioula K, Schreiber F, Jafari V, Taranko A, Karmalkar T, Kasapi A, Lenac Rovis T, Jelencic V, Bejarano DA, Fabry L, Papacharalampous M, Mattiola I, Molgora M, Hou J, Hublitz KW, Heinrich F, Guerra GM, Durek P, Patone G, Lindberg EL, Maatz H, Hölsken O, Krönke G, Mortha A, Voll RE, Clarke AJ, Hauser AE, Colonna M, Thurley K, Schlitzer A, Schneider C, Stamatiades EG, Mashreghi MF, Jonjic S, Hübner N, Diefenbach A, Kanda M, and Triantafyllopoulou A
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- Animals, Mice, Humans, Female, Epithelial Cells metabolism, Epithelial Cells immunology, Epithelial Cells pathology, Male, Lymphocytes immunology, Lymphocytes metabolism, Kidney pathology, Kidney immunology, Kidney metabolism, Antigens, Ly metabolism, Autoantibodies immunology, Autoimmunity, Single-Cell Analysis, Signal Transduction, Granulocyte-Macrophage Colony-Stimulating Factor metabolism, Mice, Inbred C57BL, Natural Cytotoxicity Triggering Receptor 1 metabolism, Lupus Nephritis immunology, Lupus Nephritis pathology, Lupus Nephritis metabolism, Macrophages immunology, Macrophages metabolism, Immunity, Innate
- Abstract
In systemic lupus erythematosus, loss of immune tolerance, autoantibody production and immune complex deposition are required but not sufficient for organ damage
1 . How inflammatory signals are initiated and amplified in the setting of autoimmunity remains elusive. Here we set out to dissect layers and hierarchies of autoimmune kidney inflammation to identify tissue-specific cellular hubs that amplify autoinflammatory responses. Using high-resolution single-cell profiling of kidney immune and parenchymal cells, in combination with antibody blockade and genetic deficiency, we show that tissue-resident NKp46+ innate lymphoid cells (ILCs) are crucial signal amplifiers of disease-associated macrophage expansion and epithelial cell injury in lupus nephritis, downstream of autoantibody production. NKp46 signalling in a distinct subset of group 1 ILCs (ILC1s) instructed an unconventional immune-regulatory transcriptional program, which included the expression of the myeloid cell growth factor CSF2. CSF2 production by NKp46+ ILCs promoted the population expansion of monocyte-derived macrophages. Blockade of the NKp46 receptor (using the antibody clone mNCR1.15; ref.2 ) or genetic deficiency of NKp46 abrogated epithelial cell injury. The same cellular and molecular patterns were operative in human lupus nephritis. Our data provide support for the idea that NKp46+ ILC1s promote parenchymal cell injury by granting monocyte-derived macrophages access to epithelial cell niches. NKp46 activation in ILC1s therefore constitutes a previously unrecognized, crucial tissue rheostat that amplifies organ damage in autoimmune hosts, with broad implications for inflammatory pathologies and therapies., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2024
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19. Advances in the Management of Spontaneous Coronary Artery Dissection (SCAD): A Comprehensive Review.
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Morena A, Giacobbe F, De Filippo O, Angelini F, Bruno F, Siliano S, Giannino G, Dusi V, Bianco M, Biolé C, Varbella F, Cerrato E, D'Ascenzo F, and De Ferrari GM
- Abstract
Spontaneous coronary artery dissection (SCAD) is a rare but significant cause of acute coronary syndrome (ACS), primarily affecting young women, often during pregnancy. Despite its rarity, SCAD poses challenges due to limited evidence on management strategies. This review examines the current state of art of SCAD management, integrating interventional and clinical insights from recent studies. The epidemiology of SCAD is related to its elusive nature, representing only a small fraction of ACS cases, while certainly underestimated. Proposed risk factors include genetic, hormonal, and environmental influences. Angiographic classification may help in SCAD diagnosis, but confirmation often relies on intracoronary imaging. Conservative management constitutes the primary approach, showing efficacy in most cases, although optimal antiplatelet therapy (APT) remains debated due to bleeding risks associated with intramural hematoma. Revascularization is reserved for high-risk cases, guided by angiographic and clinical criteria, with a focus on restoring flow rather than resolving dissection. Interventional strategies emphasize a minimalist approach to reduce complications, utilizing techniques such as balloon dilation and stent placement tailored to individual cases. Long-term outcomes highlight the risk of recurrence, necessitating vigilant follow-up and arrhythmic risk assessment, particularly in patients presenting with ventricular arrhythmias. In conclusion, SCAD management always represents a challenge for the physician, both from a clinical and interventional point of view. Recent clinical evidence and a multidisciplinary approach are vital for optimizing patient outcomes and preventing recurrence. This review offers a concise framework for navigating the complexities of SCAD management in clinical practice and proposes an algorithm for its management., Competing Interests: The authors declare no conflict of interest. Fabrizio D’Ascenzo is serving as one of the Editorial Board members of this journal. We declare that Fabrizio D’Ascenzo had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Dimitris Tousoulis., (Copyright: © 2024 The Author(s). Published by IMR Press.)
- Published
- 2024
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20. Vagal nerve stimulation in myocardial ischemia/reperfusion injury: from bench to bedside.
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Giannino G, Nocera L, Andolfatto M, Braia V, Giacobbe F, Bruno F, Saglietto A, Angelini F, De Filippo O, D'Ascenzo F, De Ferrari GM, and Dusi V
- Abstract
The identification of acute cardioprotective strategies against myocardial ischemia/reperfusion (I/R) injury that can be applied in the catheterization room is currently an unmet clinical need and several interventions evaluated in the past at the pre-clinical level have failed in translation. Autonomic imbalance, sustained by an abnormal afferent signalling, is a key component of I/R injury. Accordingly, there is a strong rationale for neuromodulation strategies, aimed at reducing sympathetic activity and/or increasing vagal tone, in this setting. In this review we focus on cervical vagal nerve stimulation (cVNS) and on transcutaneous auricular vagus nerve stimulation (taVNS); the latest has the potential to overcome several of the issues of invasive cVNS, including the possibility of being used in an acute setting, while retaining its beneficial effects. First, we discuss the pathophysiology of I/R injury, that is mostly a consequence of the overproduction of reactive oxygen species. Second, we describe the functional anatomy of the parasympathetic branch of the autonomic nervous system and the most relevant principles of bioelectronic medicine applied to electrical vagal modulation, with a particular focus on taVNS. Then, we provide a detailed and comprehensive summary of the most relevant pre-clinical studies of invasive and non-invasive VNS that support its strong cardioprotective effect whenever there is an acute or chronic cardiac injury and specifically in the setting of myocardial I/R injury. The potential benefit in the emerging field of post cardiac arrest syndrome (PCAS) is also mentioned. Indeed, electrical cVNS has a strong anti-adrenergic, anti-inflammatory, antioxidants, anti-apoptotic and pro-angiogenic effect; most of the involved molecular pathways were already directly confirmed to take place at the cardiac level for taVNS. Pre-clinical data clearly show that the sooner VNS is applied, the better the outcome, with the possibility of a marked infarct size reduction and almost complete left ventricular reverse remodelling when VNS is applied immediately before and during reperfusion. Finally, we describe in detail the limited but very promising clinical experience of taVNS in I/R injury available so far., (© 2024. The Author(s).)
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- 2024
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21. Emerin mislocalization during chromatin bridge resolution can drive prostate cancer cell invasiveness in a collagen-rich microenvironment.
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Popęda M, Kowalski K, Wenta T, Beznoussenko GV, Rychłowski M, Mironov A, Lavagnino Z, Barozzi S, Richert J, Bertolio R, Myszczyński K, Szade J, Bieńkowski M, Miszewski K, Matuszewski M, Żaczek AJ, Braga L, Del Sal G, Bednarz-Knoll N, Maiuri P, and Nastały P
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- Humans, Male, Cell Line, Tumor, Nuclear Envelope metabolism, Micronuclei, Chromosome-Defective, Cell Movement, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Prostatic Neoplasms genetics, Tumor Microenvironment, Chromatin metabolism, Membrane Proteins metabolism, Membrane Proteins genetics, Neoplasm Invasiveness, Nuclear Proteins metabolism, Nuclear Proteins genetics, Collagen metabolism
- Abstract
Micronuclei (MN) can form through many mechanisms, including the breakage of aberrant cytokinetic chromatin bridges. The frequent observation of MN in tumors suggests that they might not merely be passive elements but could instead play active roles in tumor progression. Here, we propose a mechanism through which the presence of micronuclei could induce specific phenotypic and functional changes in cells and increase the invasive potential of cancer cells. Through the integration of diverse in vitro imaging and molecular techniques supported by clinical samples from patients with prostate cancer (PCa) defined as high-risk by the D'Amico classification, we demonstrate that the resolution of chromosome bridges can result in the accumulation of Emerin and the formation of Emerin-rich MN. These structures are negative for Lamin A/C and positive for the Lamin-B receptor and Sec61β. MN can act as a protein sinks and result in the pauperization of Emerin from the nuclear envelope. The Emerin mislocalization phenotype is associated with a molecular signature that is correlated with a poor prognosis in PCa patients and is enriched in metastatic samples. Emerin mislocalization corresponds with increases in the migratory and invasive potential of tumor cells, especially in a collagen-rich microenvironment. Our study demonstrates that the mislocalization of Emerin to MN results in increased cell invasiveness, thereby worsening patient prognosis., (© 2024. The Author(s).)
- Published
- 2024
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22. Correction to: Identification of novel genes whose expression in adipose tissue affects body fat mass and distribution: an RNA-Seq and Mendelian Randomization study.
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Konigorski S, Janke J, Patone G, Bergmann MM, Lippert C, Hübner N, Kaaks R, Boeing H, and Pischon T
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- 2024
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23. Identification of novel genes whose expression in adipose tissue affects body fat mass and distribution: an RNA-Seq and Mendelian Randomization study.
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Konigorski S, Janke J, Patone G, Bergmann MM, Lippert C, Hübner N, Kaaks R, Boeing H, and Pischon T
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- Humans, Female, Male, Middle Aged, Obesity genetics, Obesity metabolism, Obesity pathology, Adult, Adiposity genetics, Aged, Body Fat Distribution, Subcutaneous Fat metabolism, Adipose Tissue metabolism, RNA-Seq, Transcriptome, Mendelian Randomization Analysis
- Abstract
Many studies have shown that abdominal adiposity is more strongly related to health risks than peripheral adiposity. However, the underlying pathways are still poorly understood. In this cross-sectional study using data from RNA-sequencing experiments and whole-body MRI scans of 200 participants in the EPIC-Potsdam cohort, our aim was to identify novel genes whose gene expression in subcutaneous adipose tissue has an effect on body fat mass (BFM) and body fat distribution (BFD). The analysis identified 625 genes associated with adiposity, of which 531 encode a known protein and 487 are novel candidate genes for obesity. Enrichment analyses indicated that BFM-associated genes were characterized by their higher than expected involvement in cellular, regulatory and immune system processes, and BFD-associated genes by their involvement in cellular, metabolic, and regulatory processes. Mendelian Randomization analyses suggested that the gene expression of 69 genes was causally related to BFM and BFD. Six genes were replicated in UK Biobank. In this study, we identified novel genes for BFM and BFD that are BFM- and BFD-specific, involved in different molecular processes, and whose up-/downregulated gene expression may causally contribute to obesity., (© 2022. The Author(s).)
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- 2024
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24. Impact of adherence to beta-blockers in all-comers ST-segment elevation myocardial infarction (STEMI) patients and according to left ventricular ejection fraction (LVEF) at discharge: results from the real-world registry FAST-STEMI.
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Giannino G, Giacobbe F, Annone U, Ravetti E, Rollo C, Nebiolo M, Troncone M, Di Vita U, Morena A, Carmagnola L, Angelini F, De Filippo O, Bruno F, Pancotti C, Gaido L, Fariselli P, D'Ascenzo PF, Giammaria M, and De Ferrari GM
- Abstract
Beta-blockers are a crucial part of post-myocardial infarction (MI) pharmacological therapy. Recent studies have raised questions about their efficacy in patients without reduced left ventricular ejection fraction (LVEF). This study aims to assess adherence to beta-blockers after discharge for ST-segment elevation myocardial infarction (STEMI) and the impact of adherence on outcomes based on LVEF at discharge. The retrospective registry FAST-STEMI evaluated real-world adherence to main cardiovascular drugs in STEMI patients between 2012 and 2017 by comparing purchased tablets to expected ones at one year through pharmacy registries. Optimal adherence was defined ≥80%. Primary outcomes included all-cause and cardiovascular death, while secondary outcomes were myocardial infarction, major/minor bleeding events, and ischemic stroke The study included 4688 patients discharged on beta-blockers. Mean age was 64 ± 12.3 years, 76% were male, and mean LVEF was 49.2 ± 8.8%. Mean adherence at one year was 87.1%. Optimal adherence was associated with lower all-cause (adjHR 0.62, 95%CI 0.41-0.92, p 0.02) and cardiovascular mortality (adjHR 0.55, 95%CI 0.26-0.98, p 0.043). In LVEF ≤40% patients, optimal adherence was linked to reduced all-cause and cardiovascular mortality but this was not found either in patients with preserved or mildly reduced LVEF. Predictors of cardiovascular mortality included older age, chronic kidney disease, male gender, and atrial fibrillation. Optimal adherence to beta-blocker therapy in all-comers STEMI patients reduced all-cause and cardiovascular mortality at 1 year; once stratified by LVEF, this effect is confirmed only in patients with reduced LVEF (< 40%) at hospital discharge., Competing Interests: Conflicts of interest: none, (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2024
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25. Single versus dual antiplatelet therapy following percutaneous left atrial appendage closure-A systematic review and meta-analysis.
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Continisio S, Montonati C, Angelini F, Bocchino PP, Carbonaro C, Giacobbe F, Dusi V, De Filippo O, Ielasi A, Giannino G, Boldi E, Fabris T, D'Ascenzo F, De Ferrari GM, and Tarantini G
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- Humans, Aged, Thrombosis prevention & control, Ischemic Stroke prevention & control, Stroke prevention & control, Observational Studies as Topic, Left Atrial Appendage Closure, Atrial Appendage surgery, Platelet Aggregation Inhibitors therapeutic use, Atrial Fibrillation, Dual Anti-Platelet Therapy methods, Hemorrhage chemically induced
- Abstract
Background: In the last few years, percutaneous LAA occlusion (LAAO) has become a plausible alternative in atrial fibrillation (AF) patients with contraindications to anticoagulation therapy. Nevertheless, the optimal antiplatelet strategy following percutaneous LAAO remains to be defined., Methods: Studies comparing single antiplatelet therapy (SAPT) versus dual antiplatelet therapy (DAPT) following LAAO were systematically searched and screened. The outcomes of interest were ischemic stroke, device-related thrombus (DRT) and major bleeding. A random-effect meta-analysis was performed comparing outcomes in both groups. The moderator effect of baseline characteristics on outcomes was evaluated by univariate meta-regression analyses., Results: Sixteen observational studies with 3255 patients treated with antiplatelet therapy (SAPT, n = 1033; DAPT, n = 2222) after LAAO were included. Mean age was 74.5 ± 8.3 years, mean CHA
2 DS2 -VASc and HAS-BLED scores were 4.3 ± 1.5 and 3.2 ± 1.0, respectively. At a weighted mean follow-up of 12.7 months, the occurrence of stroke (RR 1.33; 95% CI 0.64-2.77; p =.44), DRT (RR 1.52; 95% CI 0.90-2.58; p =.12), and the composite of stroke and DRT (RR 1.26; 95% CI 0.67-2.37; p =.47) did not differ significantly between SAPT and DAPT groups. The rate of major bleedings was also not different between groups (RR 1.41; 95% CI 0.64-3.12; p =.39)., Conclusions: Among AF patients at high bleeding risk undergoing percutaneous LAAO, a post-procedural minimalistic antiplatelet strategy with SAPT did not significantly differ from DAPT regimens regarding the rate of stroke, DRT and major bleeding., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)- Published
- 2024
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26. Impact of endothelial shear stress on coronary atherosclerotic plaque progression and composition: A meta-analysis and systematic review.
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Candreva A, Buongiorno AL, Matter MA, Rizzini ML, Giacobbe F, Ravetti E, Giannino G, Carmagnola L, Gilhofer T, Gallo D, Chiastra C, Stähli BE, Iannaccone M, Morbiducci U, Porto I, De Ferrari GM, and D'Ascenzo F
- Subjects
- Humans, Coronary Vessels diagnostic imaging, Coronary Vessels physiopathology, Plaque, Atherosclerotic physiopathology, Plaque, Atherosclerotic diagnostic imaging, Coronary Artery Disease physiopathology, Coronary Artery Disease diagnostic imaging, Endothelium, Vascular physiopathology, Disease Progression, Stress, Mechanical
- Abstract
Background and Aims: Intracoronary pressure gradients and translesional flow patterns have been correlated with coronary plaque progression and lesion destabilization. In this study, we aimed to determine the relationship between endothelial shear stress and plaque progression and to evaluate the effect of shear forces on coronary plaque features., Methods: A systematic review was conducted in medical on-line databases. Selected were studies including human participants who underwent coronary anatomy assessment with computational fluid dynamics (CFD)-based wall shear stress (WSS) calculation at baseline with anatomical evaluation at follow-up. A total of six studies were included for data extraction and analysis., Results: The meta-analysis encompassed 31'385 arterial segments from 136 patients. Lower translesional WSS values were significantly associated with a reduction in lumen area (mean difference -0.88, 95% CI -1.13 to -0.62), an increase in plaque burden (mean difference 4.32, 95% CI 1.65 to 6.99), and an increase in necrotic core area (mean difference 0.02, 95% CI 0.02 to 0.03) at follow-up imaging. Elevated WSS values were associated with an increase in lumen area (mean difference 0.78, 95% CI 0.34 to 1.21) and a reduction in both fibrofatty (mean difference -0.02, 95% CI -0.03 to -0.01) and fibrous plaque areas (mean difference -0.03, 95% CI -0.03 to -0.03)., Conclusion: This meta-analysis shows that WSS parameters were related to vulnerable plaque features at follow-up. These results emphasize the impact of endothelial shear forces on coronary plaque growth and composition. Future studies are warranted to evaluate the role of WSS in guiding clinical decision-making., Competing Interests: Declaration of competing interest A. C. has consultancy agreements with Medyria and Nanoflex. B. S. received research grants to the institution from the OPO Foundation, the Iten-Kohaut Foundation, the German Center for Cardiovascular Research (DZHK), Boston Scientific, and Edwards Lifesciences and has received consulting and speaker fees from Boston Scientific and Abbott Vascular. B.S. has been supported by the H.H. Sheikh Khalifa bin Hamad Al-Thani Research Programme. The remaining authors have nothing to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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27. Impact of statin adherence and interruption within 6 months after ST-segment elevation myocardial infarction (STEMI): Results from the real-world regional registry FAST-STEMI.
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Giacobbe F, Giannino G, Annone U, Morena A, Di Vita U, Carmagnola L, Nebiolo M, Rollo C, Ravetti E, Troncone M, Pancotti C, De Filippo O, Bruno F, Angelini F, Gaido L, Fariselli P, D'Ascenzo F, Giammaria M, and De Ferrari GM
- Subjects
- Humans, Male, Female, Aged, Middle Aged, Follow-Up Studies, Time Factors, Treatment Outcome, ST Elevation Myocardial Infarction drug therapy, ST Elevation Myocardial Infarction mortality, Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Registries, Medication Adherence statistics & numerical data
- Abstract
Background: The impact of statin therapy on cardiovascular outcomes after ST-elevation acute myocardial infarction (STEMI) in real- world patients is understudied., Aims: To identify predictors of low adherence and discontinuation to statin therapy within 6 months after STEMI and to estimate their impact on cardiovascular outcomes at one year follow-up., Methods: We evaluated real-world adherence to statin therapy by comparing the number of bought tablets to the expected ones at 1 year follow-up through pharmacy registries. A total of 6043 STEMI patients admitted from 2012 to 2017 were enrolled in the FAST STEMI registry and followed up for 4,7 ± 1,6 years; 304 patients with intraprocedural and intrahospital deaths were excluded. The main outcomes evaluated were all-cause death, cardiovascular death, myocardial infarction, major and minor bleeding events, and ischemic stroke. The compliance cut-off chosen was 80% as mainly reported in literature., Results: From a total of 5744 patients, 418 (7,2%) patients interrupted statin therapy within 6 months after STEMI, whereas 3337 (58,1%) presented >80% adherence to statin therapy. Statin optimal adherence (>80%) resulted as protective factor towards both cardiovascular (0.1% vs 4.6%; AdjHR 0.025, 95%CI 0.008-0.079, p < 0.001) and all-cause mortality (0.3% vs 13.4%; Adj HR 0.032, 95%CI 0.018-0.059, p < 0.001) at 1 year follow-up. Further, a significant reduction of ischemic stroke incidence (1% vs 2.5%, p = 0.001) was seen in the optimal adherent group. Statin discontinuation within 6 months after STEMI showed an increase of both cardiovascular (5% vs 1.7%; AdjHR 2.23; 95%CI 1.37-3.65; p = 0,001) and all-cause mortality (14.8% vs 5.1%, AdjHR 2.32; 95%CI 1.73-3.11; p 〈0,001) at 1 year follow-up. After multivariate analysis age over 75 years old, known ischemic cardiopathy and female gender resulted as predictors of therapy discontinuation. Age over 75 years old, chronic kidney disease, previous atrial fibrillation, vasculopathy, known ischemic cardiopathy were found to be predictors of low statin adherence., Conclusions: n our real-world registry low statin adherence and discontinuation therapy within 6 months after STEMI were independently associated to an increase of cardiovascular and all-cause mortality at 1 year follow-up. Low statin adherence led to higher rates of ischemic stroke., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)
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- 2024
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28. ALCAM-mediated cDC1 CD8 T cells interactions are suppressed in advanced lung tumors.
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Morosi LG, Piperno GM, López L, Amadio R, Joshi S, Rustighi A, Del Sal G, and Benvenuti F
- Subjects
- Animals, Humans, Mice, Cell Adhesion Molecules, Neuronal metabolism, Cell Adhesion Molecules, Neuronal genetics, Cell Communication immunology, Activated-Leukocyte Cell Adhesion Molecule, Antigens, CD genetics, Antigens, CD immunology, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung immunology, Carcinoma, Non-Small-Cell Lung pathology, CD8-Positive T-Lymphocytes immunology, Dendritic Cells immunology, Lung Neoplasms genetics, Lung Neoplasms immunology, Lung Neoplasms pathology
- Abstract
Conventional type 1 dendritic cells (cDC1) are critical regulators of anti-tumoral T-cell responses. The structure and abundance of intercellular contacts between cDC1 and CD8 T cells in cancer tissues is important to determine the outcome of the T-cell response. However, the molecular determinants controlling the stability of cDC1-CD8 interactions during cancer progression remain poorly investigated. Here, we generated a genetic model of non-small cell lung cancer crossed to a fluorescent cDC1 reporter (KP-XCR1
venus ) to allow the detection of cDC1-CD8T cell clusters in tumor tissues across tumor stages. We found that cDC1-CD8 clusters are abundant and productive at the early stages of tumor development but progressively diminish in advanced tumors. Transcriptional profiling and flow cytometry identified the adhesion molecule ALCAM/CD166 (Activated Leukocyte Cell Adhesion Molecule, ligand of CD6) as highly expressed by lung cDC1 and significantly downregulated in advanced tumors. Analysis of human datasets indicated that ALCAM is downregulated in non-small cell lung cancer and its expression correlates to better prognosis. Mechanistically, triggering ALCAM on lung cDC1 induces cytoskeletal remodeling and contact formation whereas its blockade prevents T-cell activation. Together, our results indicate that ALCAM is important to stabilize cDC1-CD8 interactions at early tumor stages, while its loss in advanced tumors contributes to immune evasion., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)- Published
- 2024
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29. Safety and efficacy of drug-eluting stents for patients at high risk of bleedings: A network meta-analysis.
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Giacobbe F, Valente E, Morena A, Nebiolo M, Giannino G, De Filippo O, Bruno F, Isaevska E, Richiardi L, Iannaccone M, Zoccai GB, Burzotta F, D'Ascenzo F, and Ferrari GM
- Subjects
- Humans, Coronary Thrombosis etiology, Coronary Thrombosis prevention & control, Dual Anti-Platelet Therapy, Prosthesis Design, Randomized Controlled Trials as Topic, Risk Factors, Time Factors, Treatment Outcome, Coronary Artery Disease therapy, Drug-Eluting Stents, Hemorrhage prevention & control, Network Meta-Analysis, Percutaneous Coronary Intervention adverse effects, Percutaneous Coronary Intervention instrumentation, Platelet Aggregation Inhibitors adverse effects, Platelet Aggregation Inhibitors administration & dosage
- Abstract
Introduction: Among different coronary stents implanted in High Bleeding Risk (HBR) patients with an indication for short antiplatelet therapy, no comparisons in terms of efficacy have been provided., Methods: A Network Meta Analysis was performed including all randomized controlled trials comparing different coronary stents evaluated in HBR patients. Major Adverse Cardiovascular Events (MACEs) as defined by each included trial were the primary end point, whereas TLR (target lesion revascularization), TVR (target vessel revascularization), stent thrombosis and total and major (BARC3-5) bleedings were the secondary ones., Results: A total of four studies (ONYX ONE, LEADERS FREE, SENIOR and HBR in BIO-RESORT) including 6637 patients were analyzed with different kind of stents and dual antiplatelet therapy (DAPT) length (1 or 6 months) on 12 months follow-up. About one-third of these patients were defined HBR due to indication for oral anticoagulation. All drug eluting stents (DESs) reduced risk of MACE compared to Bare Metal Stents (BMSs) when followed by a 1-month DAPT. At SUCRA analysis, Orsiro was the device with the highest probability of performing best. Rates of TLR and TVR were significantly lower when using Resolute Onyx, Synergy and BioFreedom stents in comparison to BMS when followed by 1-month DAPT, with Synergy ranking best. Synergy also showed a significantly lower number of stent thrombosis compared to BMS (RR 0.28, 95% CI 0.06-0.93), while Orsiro and Resolute Integrity showed the highest probability of performing best., Conclusion: In HBRs patients, all DESs were superior to BMSs in terms of efficacy and safety. Among DESs, Orsiro was the one with the highest ranking in terms of MACE, mainly driven by a reduced incidence of repeated revascularization and stent thrombosis., (© 2024 Wiley Periodicals LLC.)
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- 2024
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30. Gender differences in the development of heart failure after acute coronary syndrome: Insight from the CORALYS registry.
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Elia E, Bruno F, Crimi G, Wańha W, Leonardi S, Mauro M, Raposeiras Roubin S, Fabris E, Giannino G, Mancone M, Severino P, Truffa A, De Filippo O, Huczek Z, Mazurek M, Gaibazzi N, Ielasi A, Cortese B, Borin A, Núñez-Gil IJ, Marengo G, Melis D, Ugo F, Bianco M, Barbieri L, Marchini F, Desperak P, Morici N, Scaglione M, Gąsior M, Gallone G, Lopiano C, Stefanini G, Campo G, Wojakowski W, Abu-Assi E, Sinagra G, de Ferrari GM, Porto I, and D'Ascenzo F
- Subjects
- Female, Humans, Male, Registries, Retrospective Studies, Sex Factors, Stroke Volume, Ventricular Function, Left, Acute Coronary Syndrome diagnosis, Acute Coronary Syndrome epidemiology, Acute Coronary Syndrome complications, Diabetes Mellitus etiology, Heart Failure diagnosis, Heart Failure epidemiology, Heart Failure etiology, Myocardial Infarction epidemiology, Percutaneous Coronary Intervention adverse effects
- Abstract
Background: Impact of gender on heart remodeling after acute coronary syndrome (ACS) and consequently on development of heart failure (HF) remains to be elucidated., Methods: CORALYS is a multicenter, retrospective, observational registry enrolling consecutive patients admitted for ACS and treated with percutaneous coronary intervention. HF hospitalization was the primary endpoint while all-cause mortality and the composite endpoint of incidence of first HF hospitalization and cardiovascular mortality were the secondary ones., Results: Among 14,699 patients enrolled in CORALYS registry, 4578 (31%) were women and 10,121 (69%) males. Women were older, had more frequently hypertension and diabetes and less frequently smoking habit. History of myocardial infarction (MI), STEMI at admission and multivessel disease were less common in women. After median follow up of 2.9 ± 1.8 years, women had higher incidence of primary and secondary endpoints and female sex was an independent predictor of HF hospitalization (HR 1.26;1.05-1.50; p = 0.011) and cardiovascular death/HF hospitalization (HR 1.18;1.02-1.37; p = 0.022). At multivariable analysis women and men share as predictors of HF diabetes, history of cancer, chronic kidney disease, atrial fibrillation, complete revascularization and left ventricular ejection fraction. Chronic obstructive pulmonary disease (HR 2.34;1.70-3.22, p < 0.001) and diuretics treatment (HR 1.61;1.27-2.04, p < 0.001) were predictor of HF in men, while history of previous MI (HR 1.46;1.08-1.97, p = 0.015) and treatment with inhibitors of renin-angiotensin system (HR 0.69;0,49-0.96 all 95% CI, p = 0.030) in women., Conclusions: Women are at increased risk of HF after ACS and gender seems to be an outcome-modifier of the relationship between a variable and primary outcome., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)
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- 2024
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31. The Intrinsic Cardiac Nervous System: From Pathophysiology to Therapeutic Implications.
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Giannino G, Braia V, Griffith Brookles C, Giacobbe F, D'Ascenzo F, Angelini F, Saglietto A, De Ferrari GM, and Dusi V
- Abstract
The cardiac autonomic nervous system (CANS) plays a pivotal role in cardiac homeostasis as well as in cardiac pathology. The first level of cardiac autonomic control, the intrinsic cardiac nervous system (ICNS), is located within the epicardial fat pads and is physically organized in ganglionated plexi (GPs). The ICNS system does not only contain parasympathetic cardiac efferent neurons, as long believed, but also afferent neurons and local circuit neurons. Thanks to its high degree of connectivity, combined with neuronal plasticity and memory capacity, the ICNS allows for a beat-to-beat control of all cardiac functions and responses as well as integration with extracardiac and higher centers for longer-term cardiovascular reflexes. The present review provides a detailed overview of the current knowledge of the bidirectional connection between the ICNS and the most studied cardiac pathologies/conditions (myocardial infarction, heart failure, arrhythmias and heart transplant) and the potential therapeutic implications. Indeed, GP modulation with efferent activity inhibition, differently achieved, has been studied for atrial fibrillation and functional bradyarrhythmias, while GP modulation with efferent activity stimulation has been evaluated for myocardial infarction, heart failure and ventricular arrhythmias. Electrical therapy has the unique potential to allow for both kinds of ICNS modulation while preserving the anatomical integrity of the system.
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- 2024
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32. NOTCH localizes to mitochondria through the TBC1D15-FIS1 interaction and is stabilized via blockade of E3 ligase and CDK8 recruitment to reprogram tumor-initiating cells.
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Choi HY, Zhu Y, Zhao X, Mehta S, Hernandez JC, Lee JJ, Kou Y, Machida R, Giacca M, Del Sal G, Ray R, Eoh H, Tahara SM, Chen L, Tsukamoto H, and Machida K
- Subjects
- Humans, Animals, Mice, Mitochondrial Membranes, Phosphorylation, Chromatin Immunoprecipitation, Disease Models, Animal, Membrane Proteins genetics, Mitochondrial Proteins, Cyclin-Dependent Kinase 8, GTPase-Activating Proteins, Cyclin-Dependent Kinases, Ubiquitin-Protein Ligases genetics, Mitochondria
- Abstract
The P53-destabilizing TBC1D15-NOTCH protein interaction promotes self-renewal of tumor-initiating stem-like cells (TICs); however, the mechanisms governing the regulation of this pathway have not been fully elucidated. Here, we show that TBC1D15 stabilizes NOTCH and c-JUN through blockade of E3 ligase and CDK8 recruitment to phosphodegron sequences. Chromatin immunoprecipitation (ChIP-seq) analysis was performed to determine whether TBC1D15-dependent NOTCH1 binding occurs in TICs or non-TICs. The TIC population was isolated to evaluate TBC1D15-dependent NOTCH1 stabilization mechanisms. The tumor incidence in hepatocyte-specific triple knockout (Alb::CreERT2;Tbc1d15
Flox/Flox ;Notch1Flox/Flox ;Notch2Flox/Flox ;HCV-NS5A) Transgenic (Tg) mice and wild-type mice was compared after being fed an alcohol-containing Western diet (WD) for 12 months. The NOTCH1-TBC1D15-FIS1 interaction resulted in recruitment of mitochondria to the perinuclear region. TBC1D15 bound to full-length NUMB and to NUMB isoform 5, which lacks three Ser phosphorylation sites, and relocalized NUMB5 to mitochondria. TBC1D15 binding to NOTCH1 blocked CDK8- and CDK19-mediated phosphorylation of the NOTCH1 PEST phosphodegron to block FBW7 recruitment to Thr-2512 of NOTCH1. ChIP-seq analysis revealed that TBC1D15 and NOTCH1 regulated the expression of genes involved in mitochondrial metabolism-related pathways required for the maintenance of TICs. TBC1D15 inhibited CDK8-mediated phosphorylation to stabilize NOTCH1 and protect it from degradation The NUMB-binding oncoprotein TBC1D15 rescued NOTCH1 from NUMB-mediated ubiquitin-dependent degradation and recruited NOTCH1 to the mitochondrial outer membrane for the generation and expansion of liver TICs. A NOTCH-TBC1D15 inhibitor was found to inhibit NOTCH-dependent pathways and exhibited potent therapeutic effects in PDX mouse models. This unique targeting of the NOTCH-TBC1D15 interaction not only normalized the perinuclear localization of mitochondria but also promoted potent cytotoxic effects against TICs to eradicate patient-derived xenografts through NOTCH-dependent pathways., (© 2024. The Author(s).)- Published
- 2024
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33. EMID2 is a novel biotherapeutic for aggressive cancers identified by in vivo screening.
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Cappelletto A, Alfì E, Volf N, Vu TVA, Bortolotti F, Ciucci G, Vodret S, Fantuz M, Perin M, Colliva A, Rozzi G, Rossi M, Ruozi G, Zentilin L, Vuerich R, Borin D, Lapasin R, Piazza S, Chiesa M, Lorizio D, Triboli L, Kumar S, Morello G, Tripodo C, Pinamonti M, Piperno GM, Benvenuti F, Rustighi A, Jo H, Piccolo S, Del Sal G, Carrer A, Giacca M, and Zacchigna S
- Subjects
- Animals, Humans, Mice, Cell Nucleus, Disease Models, Animal, Early Detection of Cancer, Collagen metabolism, Cancer-Associated Fibroblasts, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms genetics
- Abstract
Background: New drugs to tackle the next pathway or mutation fueling cancer are constantly proposed, but 97% of them are doomed to fail in clinical trials, largely because they are identified by cellular or in silico screens that cannot predict their in vivo effect., Methods: We screened an Adeno-Associated Vector secretome library (> 1000 clones) directly in vivo in a mouse model of cancer and validated the therapeutic effect of the first hit, EMID2, in both orthotopic and genetic models of lung and pancreatic cancer., Results: EMID2 overexpression inhibited both tumor growth and metastatic dissemination, consistent with prolonged survival of patients with high levels of EMID2 expression in the most aggressive human cancers. Mechanistically, EMID2 inhibited TGFβ maturation and activation of cancer-associated fibroblasts, resulting in more elastic ECM and reduced levels of YAP in the nuclei of cancer cells., Conclusion: This is the first in vivo screening, precisely designed to identify proteins able to interfere with cancer cell invasiveness. EMID2 was selected as the most potent protein, in line with the emerging relevance of the tumor extracellular matrix in controlling cancer cell invasiveness and dissemination, which kills most of cancer patients., (© 2024. The Author(s).)
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- 2024
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34. Author Correction: Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth.
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Tombari C, Zannini A, Bertolio R, Pedretti S, Audano M, Triboli L, Cancila V, Vacca D, Caputo M, Donzelli S, Segatto I, Vodret S, Piazza S, Rustighi A, Mantovani F, Belletti B, Baldassarre G, Blandino G, Tripodo C, Bicciato S, Mitro N, and Del Sal G
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- 2023
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35. Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth.
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Tombari C, Zannini A, Bertolio R, Pedretti S, Audano M, Triboli L, Cancila V, Vacca D, Caputo M, Donzelli S, Segatto I, Vodret S, Piazza S, Rustighi A, Mantovani F, Belletti B, Baldassarre G, Blandino G, Tripodo C, Bicciato S, Mitro N, and Del Sal G
- Subjects
- Female, Humans, Amino Acids metabolism, Amino Acids, Essential, Glycine, Large Neutral Amino Acid-Transporter 1 genetics, Serine, Breast Neoplasms pathology, Tumor Suppressor Protein p53 genetics
- Abstract
Reprogramming of amino acid metabolism, sustained by oncogenic signaling, is crucial for cancer cell survival under nutrient limitation. Here we discovered that missense mutant p53 oncoproteins stimulate de novo serine/glycine synthesis and essential amino acids intake, promoting breast cancer growth. Mechanistically, mutant p53, unlike the wild-type counterpart, induces the expression of serine-synthesis-pathway enzymes and L-type amino acid transporter 1 (LAT1)/CD98 heavy chain heterodimer. This effect is exacerbated by amino acid shortage, representing a mutant p53-dependent metabolic adaptive response. When cells suffer amino acids scarcity, mutant p53 protein is stabilized and induces metabolic alterations and an amino acid transcriptional program that sustain cancer cell proliferation. In patient-derived tumor organoids, pharmacological targeting of either serine-synthesis-pathway and LAT1-mediated transport synergizes with amino acid shortage in blunting mutant p53-dependent growth. These findings reveal vulnerabilities potentially exploitable for tackling breast tumors bearing missense TP53 mutations., (© 2023. Springer Nature Limited.)
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- 2023
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36. Impact of diabetes on long-term outcomes of bifurcation percutaneous coronary intervention. An analysis from the BIFURCAT registry.
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Bruno F, Kang J, Elia E, Han JK, De Filippo O, Yang HM, Gallone G, Park KW, De Luca L, Kang HJ, Quadri G, Gwon HC, Chun WJ, Giannino G, Hur SH, Han SH, Truffa A, Bin Song Y, Cortese B, Choi KH, Chieffo A, Hong SJ, Di Pietro G, Doh JH, Wanha W, Nam CW, Kim HS, Mattesini A, de De Ferrari GM, Koo BK, and D'Ascenzo F
- Subjects
- Humans, Stroke Volume, Treatment Outcome, Risk Factors, Ventricular Function, Left, Registries, Retrospective Studies, Coronary Artery Disease diagnostic imaging, Coronary Artery Disease therapy, Coronary Artery Disease complications, Percutaneous Coronary Intervention adverse effects, Drug-Eluting Stents adverse effects, Myocardial Infarction etiology, Diabetes Mellitus diagnosis, Diabetes Mellitus epidemiology
- Abstract
Background: It is still unclear the impact of diabetes mellitus (DM) in complex coronary lesions treated with percutaneous coronary intervention (PCI) which themselves are at increased incidence of adverse events., Methods: BIFURCAT registry encompassed patients treated with PCI for coronary bifurcation lesion from the COBIS III and the RAIN registry. The primary endpoint was the occurrence of major cardiovascular adverse event (MACE), a composite and mutual exclusive of all-cause death or myocardial infarction (MI) or target-lesion revascularization (TLR). A total of 5537 patients were included in the analysis and 1834 (33%) suffered from DM., Results: After a median follow-up of 21 months, diabetic patients had a higher incidence of MACE (17% vs. 9%, p < 0.001), all-cause mortality (9% vs. 4%, p < 0.001), TLR (5% vs. 3%, p = 0.001), MI (4% vs. 2%, p < 0.001), and stent thrombosis (ST) (2% vs. 1%, p = 0.007). After multivariate analysis, diabetes remained significantly associated with MACE (hazard ratio [HR]: 1.37; confidence interval [CI]: 1.13-1.65; p = 0.001), all-cause death (HR: 1.65; 95% CI: 1.24-2.19, p = 0.001), TLR (HR: 1.45; CI: 1.03-2.04; p = 0.031) and ST (HR: 1.73, CI: 1.04-2.88; p = 0.036), but not with MI (HR: 1.34; CI: 0.93-1.92; p = 0.11). Among diabetics, chronic kidney disease (HR: 2.99; CI: 2.21-4.04), baseline left ventricular ejection fraction (HR: 0.98; CI: 0.97-0.99), femoral access (HR: 1.62; CI: 1.23-2.15), left main coronary artery (HR: 1.44; CI: 1.06-1.94), main branch diameter (HR: 0.79; CI: 0.66-0.94) and final kissing balloon (HR: 0.70; CI: 0.52-0.93) were independent predictors of MACE at follow-up., Conclusions: Patients with DM treated with PCI for coronary bifurcations have a worse prognosis due to higher incidence of MACE, all-cause mortality, TLR and ST compared to the non-diabetics., (© 2023 Wiley Periodicals LLC.)
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- 2023
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37. Dynamic links between mechanical forces and metabolism shape the tumor milieu.
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Bertolio R, Napoletano F, and Del Sal G
- Subjects
- Humans, Extracellular Matrix, Mutation, Tumor Microenvironment, Ecosystem, Neoplasms
- Abstract
Cell function relies on the spatiotemporal dynamics of metabolic reactions. In all physiopathological processes of tissues, mechanical forces impact the structure and function of membranes, enzymes, organelles and regulators of metabolic gene programs, thus regulating cell metabolism. In turn, metabolic pathways feedback impacts the physical properties of cell and tissues. Hence, metabolism and tissue mechanics are dynamically intertwined and continuously interact. Cancer is akin to an ecosystem, comprising tumor cells and various subpopulations of stromal cells embedded in an altered extracellular matrix. The progression of cancer, from initiation to advanced stage and metastasis, is driven by genetic mutations and crucially influenced by physical and metabolic alterations in the tumor microenvironment. These alterations also play a pivotal role in cancer cells evasion from immune surveillance and in developing resistance to treatments. Here, we highlight emerging evidence showing that mechano-metabolic circuits in cancer and stromal cells regulate multiple processes crucial for tumor progression and discuss potential approaches to improve therapeutic treatments by interfering with these circuits., Competing Interests: Declaration of competing interest Nothing declared., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
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38. Impact of Complete Revascularization on Development of Heart Failure in Patients With Acute Coronary Syndrome and Multivessel Disease: A Subanalysis of the CORALYS Registry.
- Author
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Bruno F, Marengo G, De Filippo O, Wanha W, Leonardi S, Raposeiras Roubin S, Fabris E, Popovic M, Giannino G, Truffa A, Huczek Z, Gaibazzi N, Ielasi A, Cortese B, Borin A, Núñez-Gil IJ, Melis D, Ugo F, Bianco M, Barbieri L, Marchini F, Desperak P, Montalto C, Melendo-Viu M, Elia E, Mancone M, Buono A, Ferrandez-Escarabajal M, Morici N, Scaglione M, Tuttolomondo D, Sardella G, Gasior M, Mazurek M, Gallone G, Campo G, Wojakowski W, Abu-Assi E, Sinagra G, De Ferrari GM, and D'Ascenzo F
- Subjects
- Humans, Registries, Stroke Volume, Treatment Outcome, Ventricular Function, Left, Acute Coronary Syndrome diagnosis, Acute Coronary Syndrome therapy, Coronary Artery Disease therapy, Heart Failure therapy, Percutaneous Coronary Intervention adverse effects, Percutaneous Coronary Intervention methods, ST Elevation Myocardial Infarction therapy
- Abstract
Background The impact of complete revascularization (CR) on the development of heart failure (HF) in patients with acute coronary syndrome and multivessel coronary artery disease undergoing percutaneous coronary intervention remains to be elucidated. Methods and Results Consecutive patients with acute coronary syndrome with multivessel coronary artery disease from the CORALYS (Incidence and Predictors of Heart Failure After Acute Coronary Syndrome) registry were included. Incidence of first hospitalization for HF or cardiovascular death was the primary end point. Patients were stratified according to completeness of coronary revascularization. Of 14 699 patients in the CORALYS registry, 5054 presented with multivessel disease. One thousand four hundred seventy-three (29.2%) underwent CR, while 3581 (70.8%) did not. Over 5 years follow-up, CR was associated with a reduced incidence of the primary end point (adjusted hazard ratio [HR], 0.66 [95% CI, 0.51-0.85]), first HF hospitalization (adjusted HR, 0.67 [95% CI, 0.49-0.90]) along with all-cause death and cardiovascular death alone (adjusted HR, 0.74 [95% CI, 0.56-0.97] and HR, 0.56 [95% CI, 0.38-0.84], respectively). The results were consistent in the propensity-score matching population and in inverse probability treatment weighting analysis. The benefit of CR was consistent across acute coronary syndrome presentations (HR, 0.59 [95% CI, 0.39-0.89] for ST-segment elevation myocardial infarction and HR, 0.71 [95% CI, 0.50-0.99] for non-ST-elevation acute coronary syndrome) and in patients with left ventricular ejection fraction >40% (HR, 0.52 [95% CI, 0.37-0.72]), while no benefit was observed in patients with left ventricular ejection fraction ≤40% (HR, 0.77 [95% CI, 0.37-1.10], P for interaction 0.04). Conclusions CR after acute coronary syndrome reduced the risk of first hospitalization for HF and cardiovascular death, as well as first HF hospitalization, and cardiovascular and overall death both in patients with ST-segment elevation myocardial infarction and non-ST-elevation acute coronary syndrome. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04895176.
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- 2023
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39. The Tumor Suppressor DAB2IP Is Regulated by Cell Contact and Contributes to YAP/TAZ Inhibition in Confluent Cells.
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Apollonio M, Bellazzo A, Franco N, Lombardi S, Senigagliesi B, Casalis L, Parisse P, Thalhammer A, Baj G, De Florian Fania R, Del Sal G, and Collavin L
- Abstract
External and internal mechanical forces modulate cell morphology, movement, proliferation and metabolism, and represent crucial inputs for tissue homeostasis. The transcriptional regulators YAP and TAZ are important effectors of mechanical signaling and are frequently activated in solid tumors, correlating with metastasis, chemoresistance, and shorter patient survival. YAP/TAZ activity is controlled by various pathways that sense cell shape, polarity, contacts, and mechanical tension. In tumors, aberrant YAP/TAZ activation may result from cancer-related alterations of such regulatory networks. The tumor suppressor DAB2IP is a Ras-GAP and scaffold protein that negatively modulates multiple oncogenic pathways and is frequently downregulated or inactivated in solid tumors. Here, we provide evidence that DAB2IP expression is sustained by cell confluency. We also find that DAB2IP depletion in confluent cells alters their morphology, reducing cell packing while increasing cell stiffness. Finally, we find that DAB2IP depletion in confluent cells favors YAP/TAZ nuclear localization and transcriptional activity, while its ectopic expression in subconfluent cells increases YAP/TAZ retention in the cytoplasm. Together, these data suggest that DAB2IP may function as a sensor of cell interactions, contributing to dampening cellular responses to oncogenic inputs in confluent cells and that DAB2IP loss-of-function would facilitate YAP/TAZ activation in intact epithelia, accelerating oncogenic transformation.
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- 2023
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40. Dynamic interplay between RPL3- and RPL3L-containing ribosomes modulates mitochondrial activity in the mammalian heart.
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Milenkovic I, Santos Vieira HG, Lucas MC, Ruiz-Orera J, Patone G, Kesteven S, Wu J, Feneley M, Espadas G, Sabidó E, Hübner N, van Heesch S, Völkers M, and Novoa EM
- Subjects
- Animals, Mice, Muscle, Skeletal metabolism, Protein Biosynthesis, Heart, Mitochondria metabolism, Ribosomal Proteins genetics, Ribosomal Proteins metabolism, Ribosomes genetics, Ribosomes metabolism
- Abstract
The existence of naturally occurring ribosome heterogeneity is now a well-acknowledged phenomenon. However, whether this heterogeneity leads to functionally diverse 'specialized ribosomes' is still a controversial topic. Here, we explore the biological function of RPL3L (uL3L), a ribosomal protein (RP) paralogue of RPL3 (uL3) that is exclusively expressed in skeletal muscle and heart tissues, by generating a viable homozygous Rpl3l knockout mouse strain. We identify a rescue mechanism in which, upon RPL3L depletion, RPL3 becomes up-regulated, yielding RPL3-containing ribosomes instead of RPL3L-containing ribosomes that are typically found in cardiomyocytes. Using both ribosome profiling (Ribo-seq) and a novel orthogonal approach consisting of ribosome pulldown coupled to nanopore sequencing (Nano-TRAP), we find that RPL3L modulates neither translational efficiency nor ribosome affinity towards a specific subset of transcripts. In contrast, we show that depletion of RPL3L leads to increased ribosome-mitochondria interactions in cardiomyocytes, which is accompanied by a significant increase in ATP levels, potentially as a result of fine-tuning of mitochondrial activity. Our results demonstrate that the existence of tissue-specific RP paralogues does not necessarily lead to enhanced translation of specific transcripts or modulation of translational output. Instead, we reveal a complex cellular scenario in which RPL3L modulates the expression of RPL3, which in turn affects ribosomal subcellular localization and, ultimately, mitochondrial activity., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)
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- 2023
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41. Patients with inflammatory bowel disease are at increased risk of atherothrombotic disease: A systematic review with meta-analysis.
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D'Ascenzo F, Bruno F, Iannaccone M, Testa G, De Filippo O, Giannino G, Caviglia GP, Bernstein CN, De Ferrari GM, Bugianesi E, Armandi A, and Ribaldone DG
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- Humans, Risk Factors, Inflammatory Bowel Diseases complications, Inflammatory Bowel Diseases diagnosis, Inflammatory Bowel Diseases epidemiology, Myocardial Infarction epidemiology, Stroke epidemiology, Hypertension complications, Diabetes Mellitus
- Abstract
Aims: Patients with inflammatory bowel disease (IBD) are known to be at increased risk for venous thrombosis, while their risk for arterial ischemic events is debated. The purpose of this study was to conduct a systematic review of the published literature on the risk of myocardial infarction (MI) in IBD patients and to identify any potential risk factors., Methods: The present study was performed according to PRISMA, with a systematic search on PubMed, Cochrane, and Google Scholar. Risk of MI was the primary end point, while all causes of death and stroke were secondary endpoints. Both univariate and multivariate pooled analysis were performed., Results: An overall population of 515,455 controls and 77,140 persons with IBD (26,852, 34.8% Crohn's disease, CD and 50,288, 65.2% ulcerative colitis, UC) was included. Mean age was similar across controls and IBD. Persons with CD and UC had lower rates of hypertension (14.5% vs. 14.6% vs. 25%), diabetes (2.9% vs. 5.2% vs. 9.2%) and dyslipidaemia (3.3% vs. 6.5% vs. 16.1%) compared to controls. Smoking did not significantly differ (17% vs. 17.5% vs. 10.6%). Pooled results of multivariate adjustment showed that, after a 5 years-follow-up, both CD and UC were at increased risk of MI (respectively HR 1.36 [1.12-1.64] and HR 1.24 [1.05-1.46]), of death (HR 1.55 [1.27-1.90] and HR 1.29 [1.01-1.64]), and of other CV disease as stroke (HR 1.22 [1.01-1.49] and HR 1.09 [1.03-1.15], all 95% CI)., Conclusions: Persons with IBD are at increased risk of MI, despite a lower prevalence of the classic risk factors for MI (hypertension, diabetes, dyslipidemia)., Competing Interests: Declaration of Competing Interest Conflict of interest: none declared., (Copyright © 2023 Elsevier B.V. All rights reserved.)
- Published
- 2023
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42. Apoptotic cell death in disease-Current understanding of the NCCD 2023.
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Vitale I, Pietrocola F, Guilbaud E, Aaronson SA, Abrams JM, Adam D, Agostini M, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Aqeilan RI, Arama E, Baehrecke EH, Balachandran S, Bano D, Barlev NA, Bartek J, Bazan NG, Becker C, Bernassola F, Bertrand MJM, Bianchi ME, Blagosklonny MV, Blander JM, Blandino G, Blomgren K, Borner C, Bortner CD, Bove P, Boya P, Brenner C, Broz P, Brunner T, Damgaard RB, Calin GA, Campanella M, Candi E, Carbone M, Carmona-Gutierrez D, Cecconi F, Chan FK, Chen GQ, Chen Q, Chen YH, Cheng EH, Chipuk JE, Cidlowski JA, Ciechanover A, Ciliberto G, Conrad M, Cubillos-Ruiz JR, Czabotar PE, D'Angiolella V, Daugaard M, Dawson TM, Dawson VL, De Maria R, De Strooper B, Debatin KM, Deberardinis RJ, Degterev A, Del Sal G, Deshmukh M, Di Virgilio F, Diederich M, Dixon SJ, Dynlacht BD, El-Deiry WS, Elrod JW, Engeland K, Fimia GM, Galassi C, Ganini C, Garcia-Saez AJ, Garg AD, Garrido C, Gavathiotis E, Gerlic M, Ghosh S, Green DR, Greene LA, Gronemeyer H, Häcker G, Hajnóczky G, Hardwick JM, Haupt Y, He S, Heery DM, Hengartner MO, Hetz C, Hildeman DA, Ichijo H, Inoue S, Jäättelä M, Janic A, Joseph B, Jost PJ, Kanneganti TD, Karin M, Kashkar H, Kaufmann T, Kelly GL, Kepp O, Kimchi A, Kitsis RN, Klionsky DJ, Kluck R, Krysko DV, Kulms D, Kumar S, Lavandero S, Lavrik IN, Lemasters JJ, Liccardi G, Linkermann A, Lipton SA, Lockshin RA, López-Otín C, Luedde T, MacFarlane M, Madeo F, Malorni W, Manic G, Mantovani R, Marchi S, Marine JC, Martin SJ, Martinou JC, Mastroberardino PG, Medema JP, Mehlen P, Meier P, Melino G, Melino S, Miao EA, Moll UM, Muñoz-Pinedo C, Murphy DJ, Niklison-Chirou MV, Novelli F, Núñez G, Oberst A, Ofengeim D, Opferman JT, Oren M, Pagano M, Panaretakis T, Pasparakis M, Penninger JM, Pentimalli F, Pereira DM, Pervaiz S, Peter ME, Pinton P, Porta G, Prehn JHM, Puthalakath H, Rabinovich GA, Rajalingam K, Ravichandran KS, Rehm M, Ricci JE, Rizzuto R, Robinson N, Rodrigues CMP, Rotblat B, Rothlin CV, Rubinsztein DC, Rudel T, Rufini A, Ryan KM, Sarosiek KA, Sawa A, Sayan E, Schroder K, Scorrano L, Sesti F, Shao F, Shi Y, Sica GS, Silke J, Simon HU, Sistigu A, Stephanou A, Stockwell BR, Strapazzon F, Strasser A, Sun L, Sun E, Sun Q, Szabadkai G, Tait SWG, Tang D, Tavernarakis N, Troy CM, Turk B, Urbano N, Vandenabeele P, Vanden Berghe T, Vander Heiden MG, Vanderluit JL, Verkhratsky A, Villunger A, von Karstedt S, Voss AK, Vousden KH, Vucic D, Vuri D, Wagner EF, Walczak H, Wallach D, Wang R, Wang Y, Weber A, Wood W, Yamazaki T, Yang HT, Zakeri Z, Zawacka-Pankau JE, Zhang L, Zhang H, Zhivotovsky B, Zhou W, Piacentini M, Kroemer G, and Galluzzi L
- Subjects
- Animals, Humans, Cell Death, Carcinogenesis, Mammals metabolism, Apoptosis genetics, Caspases genetics, Caspases metabolism
- Abstract
Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease., (© 2023. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)
- Published
- 2023
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43. Pathogenic variants damage cell composition and single cell transcription in cardiomyopathies.
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Reichart D, Lindberg EL, Maatz H, Miranda AMA, Viveiros A, Shvetsov N, Gärtner A, Nadelmann ER, Lee M, Kanemaru K, Ruiz-Orera J, Strohmenger V, DeLaughter DM, Patone G, Zhang H, Woehler A, Lippert C, Kim Y, Adami E, Gorham JM, Barnett SN, Brown K, Buchan RJ, Chowdhury RA, Constantinou C, Cranley J, Felkin LE, Fox H, Ghauri A, Gummert J, Kanda M, Li R, Mach L, McDonough B, Samari S, Shahriaran F, Yapp C, Stanasiuk C, Theotokis PI, Theis FJ, van den Bogaerdt A, Wakimoto H, Ware JS, Worth CL, Barton PJR, Lee YA, Teichmann SA, Milting H, Noseda M, Oudit GY, Heinig M, Seidman JG, Hubner N, and Seidman CE
- Subjects
- Atlases as Topic, Cell Nucleus genetics, Heart Ventricles, Humans, RNA-Seq, Arrhythmogenic Right Ventricular Dysplasia genetics, Cardiomyopathy, Dilated genetics, Heart Failure genetics, Single-Cell Analysis, Transcriptome
- Abstract
Pathogenic variants in genes that cause dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) convey high risks for the development of heart failure through unknown mechanisms. Using single-nucleus RNA sequencing, we characterized the transcriptome of 880,000 nuclei from 18 control and 61 failing, nonischemic human hearts with pathogenic variants in DCM and ACM genes or idiopathic disease. We performed genotype-stratified analyses of the ventricular cell lineages and transcriptional states. The resultant DCM and ACM ventricular cell atlas demonstrated distinct right and left ventricular responses, highlighting genotype-associated pathways, intercellular interactions, and differential gene expression at single-cell resolution. Together, these data illuminate both shared and distinct cellular and molecular architectures of human heart failure and suggest candidate therapeutic targets.
- Published
- 2022
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44. Ablation of lysophosphatidic acid receptor 1 attenuates hypertrophic cardiomyopathy in a mouse model.
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Axelsson Raja A, Wakimoto H, DeLaughter DM, Reichart D, Gorham J, Conner DA, Lun M, Probst CK, Sakai N, Knipe RS, Montesi SB, Shea B, Adam LP, Leinwand LA, Wan W, Choi ES, Lindberg EL, Patone G, Noseda M, Hübner N, Seidman CE, Tager AM, Seidman JG, and Ho CY
- Subjects
- Animals, Carrier Proteins, Disease Models, Animal, Endothelial Cells pathology, Fibrosis, Hypertrophy pathology, Mice, Cardiomyopathy, Hypertrophic genetics, Cardiomyopathy, Hypertrophic pathology, Receptors, Lysophosphatidic Acid genetics
- Abstract
Myocardial fibrosis is a key pathologic feature of hypertrophic cardiomyopathy (HCM). However, the fibrotic pathways activated by HCM-causing sarcomere protein gene mutations are poorly defined. Because lysophosphatidic acid is a mediator of fibrosis in multiple organs and diseases, we tested the role of the lysophosphatidic acid pathway in HCM. Lysphosphatidic acid receptor 1 (LPAR1), a cell surface receptor, is required for lysophosphatidic acid mediation of fibrosis. We bred HCM mice carrying a pathogenic myosin heavy-chain variant (403
+/- ) with Lpar1 -ablated mice to create mice carrying both genetic changes (403+/- LPAR1-/- ) and assessed development of cardiac hypertrophy and fibrosis. Compared with 403+/- LPAR1WT , 403+/- LPAR1-/- mice developed significantly less hypertrophy and fibrosis. Single-nucleus RNA sequencing of left ventricular tissue demonstrated that Lpar1 was predominantly expressed by lymphatic endothelial cells (LECs) and cardiac fibroblasts. Lpar1 ablation reduced the population of LECs, confirmed by immunofluorescence staining of the LEC markers Lyve1 and Ccl21a and, by in situ hybridization, for Reln and Ccl21a . Lpar1 ablation also altered the distribution of fibroblast cell states. FB1 and FB2 fibroblasts decreased while FB0 and FB3 fibroblasts increased. Our findings indicate that Lpar1 is expressed predominantly by LECs and fibroblasts in the heart and is required for development of hypertrophy and fibrosis in an HCM mouse model. LPAR1 antagonism, including agents in clinical trials for other fibrotic diseases, may be beneficial for HCM.- Published
- 2022
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45. ETS-related gene (ERG) undermines genome stability in mouse prostate progenitors via Gsk3β dependent Nkx3.1 degradation.
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Lorenzoni M, De Felice D, Beccaceci G, Di Donato G, Foletto V, Genovesi S, Bertossi A, Cambuli F, Lorenzin F, Savino A, Avalle L, Cimadamore A, Montironi R, Weber V, Carbone FG, Barbareschi M, Demichelis F, Romanel A, Poli V, Del Sal G, Julio MK, Gaspari M, Alaimo A, and Lunardi A
- Subjects
- Animals, Genomic Instability, Male, Mice, Oncogene Proteins, Trans-Activators metabolism, Glycogen Synthase Kinase 3 beta genetics, Homeodomain Proteins genetics, Prostate pathology, Prostatic Neoplasms pathology, Transcription Factors genetics, Transcriptional Regulator ERG genetics
- Abstract
21q22.2-3 deletion is the most common copy number alteration in prostate cancer (PCa). The genomic rearrangement results in the androgen-dependent de novo expression of ETS-related gene (ERG) in prostate cancer cells, a condition promoting tumor progression to advanced stages of the disease. Interestingly, ERG expression characterizes 5-30% of tumor precursor lesions - High Grade Prostatic Intraepithelial Neoplasia (HGPIN) - where its role remains unclear. Here, by combining organoids technology with Click-chemistry coupled Mass Spectrometry, we demonstrate a prominent role of ERG in remodeling the protein secretome of prostate progenitors. Functionally, by lowering autocrine Wnt-4 signaling, ERG represses canonical Wnt pathway in prostate progenitors, and, in turn, promotes the accumulation of DNA double strand breaks via Gsk3β-dependent degradation of the tumor suppressor Nkx3.1. On the other hand, by shaping extracellular paracrine signals, ERG strengthens the pro-oxidative transcriptional signature of inflammatory macrophages, which we demonstrate to infiltrate pre-malignant ERG positive prostate lesions. These findings highlight previously unrecognized functions of ERG in undermining adult prostate progenitor niche through cell autonomous and non-autonomous mechanisms. Overall, by supporting the survival and proliferation of prostate progenitors in the absence of growth stimuli and promoting the accumulation of DNA damage through destabilization of Nkx3.1, ERG could orchestrate the prelude to neoplastic transformation., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2022
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46. TGS1 mediates 2,2,7-trimethyl guanosine capping of the human telomerase RNA to direct telomerase dependent telomere maintenance.
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Buemi V, Schillaci O, Santorsola M, Bonazza D, Broccia PV, Zappone A, Bottin C, Dell'Omo G, Kengne S, Cacchione S, Raffa GD, Piazza S, di Fagagna FD, Benetti R, Cortale M, Zanconati F, Del Sal G, and Schoeftner S
- Subjects
- Guanosine, Humans, RNA genetics, Telomere genetics, Telomere metabolism, Telomerase genetics, Telomerase metabolism
- Abstract
Pathways that direct the selection of the telomerase-dependent or recombination-based, alternative lengthening of telomere (ALT) maintenance pathway in cancer cells are poorly understood. Using human lung cancer cells and tumor organoids we show that formation of the 2,2,7-trimethylguanosine (TMG) cap structure at the human telomerase RNA 5' end by the Trimethylguanosine Synthase 1 (TGS1) is central for recruiting telomerase to telomeres and engaging Cajal bodies in telomere maintenance. TGS1 depletion or inhibition by the natural nucleoside sinefungin impairs telomerase recruitment to telomeres leading to Exonuclease 1 mediated generation of telomere 3' end protrusions that engage in RAD51-dependent, homology directed recombination and the activation of key features of the ALT pathway. This indicates a critical role for 2,2,7-TMG capping of the RNA component of human telomerase (hTR) in enforcing telomerase-dependent telomere maintenance to restrict the formation of telomeric substrates conductive to ALT. Our work introduces a targetable pathway of telomere maintenance that holds relevance for telomere-related diseases such as cancer and aging., (© 2022. The Author(s).)
- Published
- 2022
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47. Expression of cardiovascular-related microRNAs is altered in L-arginine:glycine amidinotransferase deficient mice.
- Author
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Jensen M, Müller C, Hübner N, Patone G, Saar K, Choe CU, Schwedhelm E, and Zeller T
- Subjects
- Amidinotransferases, Animals, Arginine metabolism, Creatine metabolism, Homoarginine metabolism, Mice, Heart Failure, MicroRNAs genetics, Myocardial Infarction genetics
- Abstract
In humans and mice, L-arginine:glycine amidinotransferase (AGAT) and its metabolites homoarginine (hArg) and creatine have been linked to cardiovascular disease (CVD), specifically myocardial infarction (MI) and heart failure (HF). The underlying molecular and regulatory mechanisms, however, remain unclear. To identify potential pathways of cardiac AGAT metabolism, we sequenced microRNA (miRNA) in left ventricles of wild-type (wt) compared to AGAT-deficient (AGAT
-/- ) mice. Using literature search and validation by qPCR, we identified eight significantly regulated miRNAs in AGAT-/- mice linked to atherosclerosis, MI and HF: miR-30b, miR-31, miR-130a, miR-135a, miR-148a, miR-204, miR-298, and let-7i. Analysis of Gene Expression Omnibus (GEO) data confirmed deregulation of these miRNAs in mouse models of MI and HF. Quantification of miRNA expression by qPCR in AGAT-/- mice supplemented with creatine or hArg revealed that miR-30b, miR-31, miR-130a, miR-148a, and miR-204 were regulated by creatine, while miR-135a and miR-298 showed a trend of regulation by hArg. Finally, bioinformatics-based target prediction showed that numerous AGAT-dependent genes previously linked to CVD are likely to be regulated by the identified miRNAs. Taken together, AGAT deficiency and hArg/creatine supplementation are associated with cardiac miRNA expression which may influence cardiac (dys)function and CVD., (© 2022. The Author(s).)- Published
- 2022
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48. Loss of the E6AP Ubiquitin Ligase Induces p53-Dependent Phosphorylation of Human Papillomavirus 18 E6 in Cells Derived from Cervical Cancer.
- Author
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Vats A, Skrabar N, Del Sal G, and Banks L
- Subjects
- Cell Line, Tumor, Female, Humans, Phosphorylation, Tumor Suppressor Protein p53 metabolism, Human papillomavirus 18 metabolism, Ubiquitin-Protein Ligases genetics, Ubiquitin-Protein Ligases metabolism, Uterine Cervical Neoplasms physiopathology, Uterine Cervical Neoplasms virology
- Abstract
Cancer-causing human papillomavirus (HPV) E6 oncoproteins contain a well-characterized phosphoacceptor site within the PDZ (PSD-95/Dlg/ZO-1) binding motif (PBM) at the C terminus of the protein. Previous studies have shown that the threonine or serine residue in the E6 PBM is subject to phosphorylation by several stress-responsive cellular kinases upon the induction of DNA damage in cervical cancer-derived cells. However, there is little information about the regulation of E6 phosphorylation in the absence of DNA damage and whether there may be other pathways by which E6 is phosphorylated. In this study, we demonstrate that loss of E6AP results in a dramatic increase in the levels of phosphorylated E6 (pE6) despite the expected overall reduction in total E6 protein levels. Furthermore, phosphorylation of E6 requires transcriptionally active p53 and occurs in a manner that is dependent upon DNA-dependent protein kinase (DNA PK). These results identify a novel feedback loop, where loss of E6AP results in upregulation of p53, leading to increased levels of E6 phosphorylation, which in turn correlates with increased association with 14-3-3 and inhibition of p53 transcriptional activity. IMPORTANCE This study demonstrates that the knockdown of E6AP from cervical cancer-derived cells leads to an increase in phosphorylation of the E6 oncoprotein. We show that this phosphorylation of E6 requires p53 transcriptional activity and the enzyme DNA PK. This study therefore defines a feedback loop whereby activation of p53 can induce phosphorylation of E6 and which in turn can inhibit p53 transcriptional activity independently of E6's ability to target p53 for degradation.
- Published
- 2022
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49. The prolyl-isomerase PIN1 is essential for nuclear Lamin-B structure and function and protects heterochromatin under mechanical stress.
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Napoletano F, Ferrari Bravo G, Voto IAP, Santin A, Celora L, Campaner E, Dezi C, Bertossi A, Valentino E, Santorsola M, Rustighi A, Fajner V, Maspero E, Ansaloni F, Cancila V, Valenti CF, Santo M, Artimagnella OB, Finaurini S, Gioia U, Polo S, Sanges R, Tripodo C, Mallamaci A, Gustincich S, d'Adda di Fagagna F, Mantovani F, Specchia V, and Del Sal G
- Subjects
- Alzheimer Disease metabolism, Alzheimer Disease pathology, Animals, Cells, Cultured, Chromobox Protein Homolog 5 genetics, Chromobox Protein Homolog 5 metabolism, DNA Transposable Elements genetics, Drosophila metabolism, Drosophila Proteins antagonists & inhibitors, Drosophila Proteins genetics, Humans, Lamin Type B chemistry, Mice, Mice, Inbred C57BL, NIMA-Interacting Peptidylprolyl Isomerase antagonists & inhibitors, NIMA-Interacting Peptidylprolyl Isomerase genetics, Neocortex cytology, Neocortex metabolism, Neurons cytology, Neurons metabolism, Nuclear Envelope chemistry, Peptidylprolyl Isomerase antagonists & inhibitors, Peptidylprolyl Isomerase genetics, Phosphorylation, RNA Interference, RNA, Small Interfering metabolism, Drosophila Proteins metabolism, Heterochromatin metabolism, Lamin Type B metabolism, NIMA-Interacting Peptidylprolyl Isomerase metabolism, Peptidylprolyl Isomerase metabolism, Stress, Mechanical
- Abstract
Chromatin organization plays a crucial role in tissue homeostasis. Heterochromatin relaxation and consequent unscheduled mobilization of transposable elements (TEs) are emerging as key contributors of aging and aging-related pathologies, including Alzheimer's disease (AD) and cancer. However, the mechanisms governing heterochromatin maintenance or its relaxation in pathological conditions remain poorly understood. Here we show that PIN1, the only phosphorylation-specific cis/trans prolyl isomerase, whose loss is associated with premature aging and AD, is essential to preserve heterochromatin. We demonstrate that this PIN1 function is conserved from Drosophila to humans and prevents TE mobilization-dependent neurodegeneration and cognitive defects. Mechanistically, PIN1 maintains nuclear type-B Lamin structure and anchoring function for heterochromatin protein 1α (HP1α). This mechanism prevents nuclear envelope alterations and heterochromatin relaxation under mechanical stress, which is a key contributor to aging-related pathologies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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50. A trans locus causes a ribosomopathy in hypertrophic hearts that affects mRNA translation in a protein length-dependent fashion.
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Witte F, Ruiz-Orera J, Mattioli CC, Blachut S, Adami E, Schulz JF, Schneider-Lunitz V, Hummel O, Patone G, Mücke MB, Šilhavý J, Heinig M, Bottolo L, Sanchis D, Vingron M, Chekulaeva M, Pravenec M, Hubner N, and van Heesch S
- Subjects
- Animals, Cardiomegaly metabolism, Cardiomegaly pathology, Gene Expression Profiling, Gene Expression Regulation, Genetic Variation, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocardium metabolism, Myocardium pathology, Organelle Biogenesis, RNA, Messenger metabolism, RNA, Small Nucleolar metabolism, Rats, Rats, Inbred SHR, Rats, Transgenic, Ribosomal Proteins metabolism, Ribosomes metabolism, Ribosomes pathology, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae metabolism, Sarcomeres metabolism, Sarcomeres pathology, Cardiomegaly genetics, Peptide Chain Initiation, Translational, Quantitative Trait Loci, RNA, Messenger genetics, RNA, Small Nucleolar genetics, Ribosomal Proteins genetics, Ribosomes genetics
- Abstract
Background: Little is known about the impact of trans-acting genetic variation on the rates with which proteins are synthesized by ribosomes. Here, we investigate the influence of such distant genetic loci on the efficiency of mRNA translation and define their contribution to the development of complex disease phenotypes within a panel of rat recombinant inbred lines., Results: We identify several tissue-specific master regulatory hotspots that each control the translation rates of multiple proteins. One of these loci is restricted to hypertrophic hearts, where it drives a translatome-wide and protein length-dependent change in translational efficiency, altering the stoichiometric translation rates of sarcomere proteins. Mechanistic dissection of this locus across multiple congenic lines points to a translation machinery defect, characterized by marked differences in polysome profiles and misregulation of the small nucleolar RNA SNORA48. Strikingly, from yeast to humans, we observe reproducible protein length-dependent shifts in translational efficiency as a conserved hallmark of translation machinery mutants, including those that cause ribosomopathies. Depending on the factor mutated, a pre-existing negative correlation between protein length and translation rates could either be enhanced or reduced, which we propose to result from mRNA-specific imbalances in canonical translation initiation and reinitiation rates., Conclusions: We show that distant genetic control of mRNA translation is abundant in mammalian tissues, exemplified by a single genomic locus that triggers a translation-driven molecular mechanism. Our work illustrates the complexity through which genetic variation can drive phenotypic variability between individuals and thereby contribute to complex disease.
- Published
- 2021
- Full Text
- View/download PDF
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