65 results on '"Cavallari I"'
Search Results
2. Association between platelet reactivity and long-term bleeding complications following percutaneous coronary intervention in patients with and without diabetes
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Cavallari, I, primary, Patti, G, additional, Maddaloni, E, additional, Veneziano, F, additional, Mangiacapra, F, additional, Ricottini, E, additional, Ussia, G P, additional, and Grigioni, F, additional
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- 2021
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3. P263 - The feasibility of MicroRNA-Based Approach in Prognostic Stratification in Bladder Cancer Patients
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Di Gianfrancesco, L., Cavallari, I., Ciminale, V., Crestani, A., Amodeo, A., Corsi, P., Lista, G., De Marchi, D., Miglioranza, E., Cargnel, C.G., Vitelli, F.D., Simonetti, F., and Porreca, A.
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- 2023
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4. Effect of body mass index on ischemic and bleeding events in patients presenting with acute coronary syndromes: insights from the START-ANTIPLATELET registry
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Moscarella, E, primary, Calabro, P, additional, Gragnano, F, additional, Cesaro, A, additional, Pafundi, P.C, additional, Patti, G, additional, Cavallari, I, additional, Antonucci, E, additional, Cirillo, P, additional, Pignatelli, P, additional, Palareti, G, additional, Sasso, F.C, additional, Pengo, V, additional, Gresele, P, additional, and Marcucci, R, additional
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- 2020
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5. Ischemic and bleeding risk stratification in diabetic patients after acute coronary syndrome based on insulin requirement
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Cavallari, I, primary, Sagazio, E, additional, Antonucci, E, additional, Calabro', P, additional, Gragnano, F, additional, Cirillo, P, additional, Gresele, P, additional, Palareti, G, additional, Pengo, V, additional, Pignatelli, P, additional, Marcucci, R, additional, and Patti, G, additional
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- 2020
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6. 3054Efficacy and safety of non-vitamin K oral anticoagulants in patients with atrial fibrillation and cancer
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Cavallari, I, primary, Verolino, G, additional, and Patti, G, additional
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- 2019
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7. Post-transcriptional Regulation of HTLV Gene Expression: Rex to the Rescue
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D'Agostino, D. M., Cavallari, I., Romanelli, M. G., and Ciminale, V.
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Microbiology (medical) ,RNA export ,splicing ,HTLV-2 ,HTLV-1 ,viruses ,Mini Review ,Rex ,biochemical phenomena, metabolism, and nutrition ,Splicing ,Microbiology - Abstract
Human T-lymphotropic virus type 1 (HTLV-1) and other members of the Deltaretrovirus genus code for a regulatory protein named Rex that binds to the Rex-responsive element present on viral mRNAs. Rex rescues viral mRNAs from complete splicing or degradation and guides them to the cytoplasm for translation. The activity of Rex is essential for expression of viral transcripts coding for the virion components and thus represents a potential target for virus eradication. We present an overview of the functional properties of the HTLV-1 and HTLV-2 Rex proteins (Rex-1 and Rex-2), outline mechanisms controlling Rex function, and discuss similarities and differences in the sequences of Rex coded by HTLV-1, -2, -3, and -4 that may influence their molecular anatomy and functional properties.
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- 2019
8. Prevention of atherothrombotic events in patients with diabetes mellitus: from antithrombotic therapies to new-generation glucose-lowering drugs
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Patti, G., Cavallari, I., Andreotti, F., Calabrò, P., Cirillo, P., Denas, G., Galli, M., Golia, E., Maddaloni, E., Marcucci, R., Parato, V. M., Pengo, V., Prisco, D., Ricottini, E., Renda, G., Santilli, F., Simeone, P., De Caterina, R., on behalf of the Working Group on Thrombosis of the Italian Society of Cardiology, Patti, Giuseppe, Cavallari, Ilaria, Andreotti, Felicita, Calabrò, Paolo, Cirillo, Plinio, Denas, Gentian, Galli, Mattia, Golia, Enrica, Maddaloni, Ernesto, Marcucci, Rossella, Parato, Vito Maurizio, Pengo, Vittorio, Prisco, Domenico, Ricottini, Elisabetta, Renda, Giulia, Santilli, Francesca, Simeone, Paola, and De Caterina, Raffaele
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0301 basic medicine ,diabetes ,thrombosis ,cardiovascular events ,antithrombotic drugs ,medicine.medical_specialty ,Disease ,030204 cardiovascular system & hematology ,blood coagulation ,Coronary artery disease ,03 medical and health sciences ,0302 clinical medicine ,Fibrinolytic Agents ,Risk Factors ,Diabetes mellitus ,Antithrombotic ,Diabetes Mellitus ,Secondary Prevention ,medicine ,Humans ,Hypoglycemic Agents ,atherothrombotic events, diabetes mellitus, prevention, glucose-lowering drugs ,Risk factor ,Intensive care medicine ,Diabetes, Cardiovascular Disease, Thrombosis ,Preventive medicine ,business.industry ,Consensus Statement ,Thrombosis ,Type 2 diabetes ,Atrial fibrillation ,Guideline ,medicine.disease ,Type 1 diabetes ,030104 developmental biology ,Cardiovascular Diseases ,Practice Guidelines as Topic ,Settore MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE ,Drug therapy ,Cardiology and Cardiovascular Medicine ,business - Abstract
Diabetes mellitus is an important risk factor for a first cardiovascular event and for worse outcomes after a cardiovascular event has occurred. This situation might be caused, at least in part, by the prothrombotic status observed in patients with diabetes. Therefore, contemporary antithrombotic strategies, including more potent agents or drug combinations, might provide greater clinical benefit in patients with diabetes than in those without diabetes. In this Consensus Statement, our Working Group explores the mechanisms of platelet and coagulation activity, the current debate on antiplatelet therapy in primary cardiovascular disease prevention, and the benefit of various antithrombotic approaches in secondary prevention of cardiovascular disease in patients with diabetes. While acknowledging that current data are often derived from underpowered, observational studies or subgroup analyses of larger trials, we propose antithrombotic strategies for patients with diabetes in various cardiovascular settings (primary prevention, stable coronary artery disease, acute coronary syndromes, ischaemic stroke and transient ischaemic attack, peripheral artery disease, atrial fibrillation, and venous thromboembolism). Finally, we summarize the improvements in cardiovascular outcomes observed with the latest glucose-lowering drugs, and on the basis of the available evidence, we expand and integrate current guideline recommendations on antithrombotic strategies in patients with diabetes for both primary and secondary prevention of cardiovascular disease., Patients with diabetes mellitus have a prothrombotic status that increases the risk of cardiovascular events and worsens prognosis after these events. In this Consensus Statement, the Working Group on Thrombosis of the Italian Society of Cardiology proposes antithrombotic strategies for patients with diabetes in various cardiovascular settings.
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- 2019
9. P3837Net clinical benefit of NOACs vs. VKAs in elderly patients with atrial fibrillation: a pooled analysis from the real-world PREFER in AF and PREFER in AF PROLONGATION registries
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Cavallari, I, primary, Patti, G, additional, Pecen, L, additional, Lucerna, M, additional, Huber, K, additional, Rohla, M, additional, Renda, G, additional, Siller-Matula, J, additional, Ricci, F, additional, Kirkhhof, P, additional, and De Caterina, R, additional
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- 2018
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10. P5153Net clinical benefit of oral anticoagulation in very elderly patients with atrial fibrillation: a sub-analysis from the PREFER in AF registry
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Cavallari, I., primary, Patti, G., additional, Lucerna, M., additional, Pecen, L., additional, Siller-Matula, J., additional, Kirchhof, P., additional, and De Caterina, R., additional
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- 2017
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11. Differential expression of menin in sporadic pituitary adenomas.
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Theodoropoulou, M, primary, Cavallari, I, additional, Barzon, L, additional, D'Agostino, D M, additional, Ferro, T, additional, Arzberger, T, additional, Grübler, Y, additional, Schaaf, L, additional, Losa, M, additional, Fallo, F, additional, Ciminale, V, additional, Stalla, G K, additional, and Pagotto, U, additional
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- 2004
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12. Kinetics and intracellular compartmentalization of HTLV-1 gene expression
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D'Agostino Donna M, Taylor Graham P, Jacobson Steven, Tanaka Yuetsu, Toffolo Gianna M, Toulza Frederic, Silic-Benussi Micol, Corradin Alberto, Cavallari Ilaria, Rende Francesca, Bangham Charles R M, and Ciminale Vincenzo
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2011
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13. Analysis of temporal expression of HTLV-2 reveals similarities and functional differences from HTLV-1
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Bertazzoni Umberto, Ciminale Vincenzo, Casoli Claudio, Cavallari Ilaria, Ronzi Paola, Rende Francesca, Cotena Alessia, and Bender Cecilia
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2011
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14. Kinetics of human-T cell leukemia virus type 2 (HTLV-2) mRNA expression in PBMCs isolated from infected subjects
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Casoli Claudio, Ciminale Vincenzo, Cavallari Ilaria, Turci Marco, Cotena Alessia, Rende Francesca, Ronzi Paola, Bender Cecilia, and Bertazzoni Umberto
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2009
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15. Temporal regulation of HTLV-2 expression in infected cell lines and patients: evidence for distinct expression kinetics with nuclear accumulation of APH-2 mRNA
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Bender Cecilia, Rende Francesca, Cotena Alessia, Righi Paola, Ronzi Paola, Cavallari Ilaria, Casoli Claudio, Ciminale Vincenzo, and Bertazzoni Umberto
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Immunologic diseases. Allergy ,RC581-607 - Abstract
Abstract Background Human T-cell leukemia virus types 1 and 2 (HTLV-1 and HTLV-2) are delta retroviruses with similar genetic organization. Although both viruses immortalize T-cells in vitro, they exhibit distinct pathogenic potential in vivo. To search for possible differences in its expression strategy with respect to HTLV-1, we investigated the pattern of HTLV-2 expression in infected cell lines and peripheral blood mononuclear cells (PBMCs) from infected patients using splice site-specific quantitative RT-PCR. Findings A novel alternative splice acceptor site for exon 2 was identified; its usage in env transcripts was found to be subtype-specific. Time-course analysis revealed a two-phase expression kinetics in an infected cell line and in PBMCs of two of the three patients examined; this pattern was reminiscent of HTLV-1. In addition, the minus-strand APH2 transcript was mainly detected in the nucleus, a feature that was similar to its HTLV-1 orthologue HBZ. In contrast to HTLV-1, expression of the mRNA encoding the main regulatory proteins Tax and Rex and that of the mRNAs encoding the p28 and truncated Rex inhibitors is skewed towards p28/truncated Rex inhibitors in HTLV-2. Conclusion Our data suggest a general converging pattern of expression of HTLV-2 and HTLV-1 and highlight peculiar differences in the expression of regulatory proteins that might influence the pathobiology of these viruses.
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- 2012
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16. Questions and Answers on Practical Thrombotic Issues in SARS-CoV-2 Infection: A Guidance Document from the Italian Working Group on Atherosclerosis, Thrombosis and Vascular Biology
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Andrea Rubboli, Veronica Lio, Giuseppe Di Pasquale, Felice Gragnano, Letizia Riva, Vittorio Pengo, Paolo Calabrò, Giuseppe Patti, Ilaria Cavallari, Patti, G., Lio, V., Cavallari, I., Gragnano, F., Riva, L., Calabro, P., Di Pasquale, G., Pengo, V., and Rubboli, A.
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medicine.medical_specialty ,medicine.drug_class ,MEDLINE ,Review Article ,Sex Factor ,030204 cardiovascular system & hematology ,Antiviral Agents ,Chemoprevention ,Severity of Illness Index ,03 medical and health sciences ,Sex Factors ,0302 clinical medicine ,Pharmacotherapy ,Risk Factors ,Atrial Fibrillation ,Severity of illness ,Pandemic ,Antithrombotic ,medicine ,Humans ,Drug Interactions ,Age Factor ,Pharmacology (medical) ,030212 general & internal medicine ,Intensive care medicine ,Pandemics ,Antiviral Agent ,Disseminated intravascular coagulation ,Risk Management ,SARS-CoV-2 ,business.industry ,Risk Factor ,Anti-Inflammatory Agents, Non-Steroidal ,Anticoagulant ,Age Factors ,Anticoagulants ,COVID-19 ,Thrombosis ,General Medicine ,Disseminated Intravascular Coagulation ,medicine.disease ,Drug Interaction ,Italy ,Cardiology and Cardiovascular Medicine ,business ,Human - Abstract
In patients with coronavirus disease 2019 (COVID-19), the prevalence of pre-existing cardiovascular diseases is elevated. Moreover, various features, also including pro-thrombotic status, further predispose these patients to increased risk of ischemic cardiovascular events. Thus, the identification of optimal antithrombotic strategies in terms of the risk–benefit ratio and outcome improvement in this setting is crucial. However, debated issues on antithrombotic therapies in patients with COVID-19 are multiple and relevant. In this article, we provide ten questions and answers on risk stratification and antiplatelet/anticoagulant treatments in patients at risk of/with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection based on the scientific evidence gathered during the pandemic.
- Published
- 2020
17. A Prospective Study to Evaluate the Effectiveness of Edoxaban for the Resolution of Left Atrial Thrombosis in Patients with Atrial Fibrillation
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Giuseppe Patti, Vito Maurizio Parato, Ilaria Cavallari, Paolo Calabrò, Vincenzo Russo, Giulia Renda, Felice Gragnano, Vittorio Pengo, Antonio D’Onofrio, Massimo Grimaldi, Raffaele De Caterina, Patti, G., Parato, V. M., Cavallari, I., Calabro, P., Russo, V., Renda, G., Gragnano, F., Pengo, V., D'Onofrio, A., Grimaldi, M., and De Caterina, R.
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vitamin K antagonists ,left atrial appendage ,edoxaban ,cardiovascular system ,non-vitamin K antagonist oral anticoagulant ,thrombosi ,atrial fibrillation ,thrombus resolution ,cardiovascular diseases ,General Medicine ,left atrium ,thrombosis ,non-vitamin K antagonist oral anticoagulants - Abstract
Available evidence on left atrial (LA) thrombus dissolution in patients with atrial fibrillation (AF) largely refers to the use of vitamin K antagonist oral anticoagulants (VKAs), showing >50% thrombus resolution over a 4-week to 12-month treatment period. Available data on non-vitamin K antagonist anticoagulants (NOACs) in this setting are limited and derive from isolated case reports or observational small-sized investigations with dabigatran, rivaroxaban or apixaban. The aim of this study was to investigate the extent of thrombus resolution with edoxaban therapy in patients with AF and LA thrombosis. We conducted a prospective, observational, open-label pilot study in seven Italian institutions. We included a total of 25 patients with non-valvular AF and LA (or left atrial appendage (LAA)) thrombosis, documented by transesophageal echocardiography (TEE). All patients received edoxaban OD treatment (n = 23 on 60 mg daily; n = 2 on 30 mg daily) and underwent TEE examination after 4 weeks. The primary endpoint was the percentage of patients with complete thrombus resolution by TEE imaging at 4 weeks. The mean age of the study population was 68.3 ± 10.8 years with a female population of 16%. AF was permanent in all cases, with a mean arrhythmia duration of 4.3 ± 1.7 years. CHA2DS2-VASc and HAS-BLED scores were 3.2 ± 1.5 and 1.9 ± 1.1, respectively. We were able to demonstrate a complete thrombus resolution in 14 patients (56%) at 4 weeks. In patients with residual atrial thrombosis (n = 11), we observed a 15.4 ± 14.9% reduction in the thrombus area from baseline. As compared with patients without thrombus dissolution, those with thrombus resolution had a numerically lower-indexed LA diameter (27.9 ± 9.3 vs 34.8 ± 16.1 mm/m2), a smaller maximum thrombus area at baseline (45.5 ± 44.6 vs 63.9 ± 43.5 mm2), a higher left ventricular ejection fraction (47.4 ± 21.0% vs 38.4 ± 20.6%) and higher maximum LAA flow velocities (26.3 ± 15.2 vs 19.3 ± 10.0 cm/s). Figures on the percentage of thrombus resolution in this study are comparable to those reported in the literature for the other OACs. We conclude that, in patients with AF, the use of edoxaban is associated with a >50% resolution of atrial thrombus at 4 weeks, similar to studies using VKAs and the other NOACs (ClinicalTrials.gov identifier number: NCT034899395).
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- 2022
18. Differential expression of menin in sporadic pituitary adenomas
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Uberto Pagotto, Ludwig Schaaf, Thomas Arzberger, Vincenzo Ciminale, Yvonne Grübler, Marco Losa, Francesco Fallo, Tiziana Ferro, Marily Theodoropoulou, Luisa Barzon, Ilaria Cavallari, Gk Stalla, Dm D'Agostino, Theodoropoulou, M., Cavallari, I., Barzon, L., D'Agostino, D. M., Ferro, T., Arzberger, T., Grübler, Y., Schaaf, L., Losa, M., Fallo, F., Ciminale, V., Stalla, G. K., Pagotto, U., THEODOROPOULOU M, CAVALLARI I, BARZON L, D'AGOSTINO DM, FERRO T, ARZBERGER T, GRUBLER Y, SCHAAF L, LOSA M, FALLO F, CIMINALE V, STALLA GK, and PAGOTTO U.
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Adenoma ,Adult ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system ,Pathology ,medicine.medical_specialty ,Pituitary gland ,Cancer Research ,Adolescent ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,Pituitary neoplasm ,Biology ,Immunoenzyme Techniques ,Endocrinology ,Proto-Oncogene Proteins ,medicine ,Humans ,Genes, Tumor Suppressor ,Neoplasm Invasiveness ,Pituitary Neoplasms ,MEN1 ,Nuclear protein ,Multiple endocrine neoplasia ,Aged ,Aged, 80 and over ,Middle Aged ,medicine.disease ,medicine.anatomical_structure ,Oncology ,Pituitary Gland ,Pituitary carcinoma ,Immunohistochemistry ,Female - Abstract
Pituitary adenomas represent one of the key features of multiple endocrine neoplasia type 1. The gene involved in this syndrome (MEN1) is a putative tumor suppressor, that codes for a 610-amino acid nuclear protein termed 'menin'. Analyses of sporadic pituitary adenomas have so far failed to reveal MEN1 mutations or defects in MEN1 transcription in these tumors. In the present study we detected menin protein expression in a panel of normal and tumoral pituitary tissues, using a monoclonal antibody against the carboxy-terminus of menin. In the normal human pituitary gland, strong nuclear staining for menin was detectable in the majority of the endocrine cells of the anterior lobe, without a clear association with a particular hormone-producing type. In sporadic pituitary adenomas, menin expression was variable, with a high percentage of cases demonstrating a significant decrease in menin immunoreactivity when compared with the normal pituitary. Interestingly, metastatic tissues derived from one pituitary carcinoma had no detectable menin levels. Altogether, our data provide the first information regarding the status of menin expression in human normal and neoplastic pituitary as determined by immunohistochemistry (IHC).
- Published
- 2004
19. Vitamin D and Diabetes Mellitus
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Caterina Conte, Nicola Napoli, Ernesto Maddaloni, Ilaria Cavallari, Giustina A, Bilezikian JP., Maddaloni, E, Cavallari, I, Napoli, N, and Conte, C
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Type 1 diabetes ,business.industry ,030209 endocrinology & metabolism ,Type 2 diabetes ,030204 cardiovascular system & hematology ,medicine.disease ,Bioinformatics ,law.invention ,Clinical trial ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Randomized controlled trial ,law ,Diabetes mellitus ,medicine ,Vitamin D and neurology ,Glucose homeostasis ,business - Abstract
Vitamin D has been suggested as a protective compound for diabetes mellitus. Several mechanisms linking vitamin D to the regulation of the immune response support a role for vitamin D in the pathogenesis of autoimmune diabetes. Epidemiological evidence and observational studies suggesting that adequate vitamin D status is related to decreased risk of developing type 1 diabetes further corroborates this concept. However, only few and mostly underpowered randomized clinical trials have been conducted to test the effectiveness of vitamin D supplementation in autoimmune diabetes, with disappointing results. Similarly, recent evidence linking vitamin D action to insulin secretion and sensitivity led to the hypothesis that this compound may play a key role in the regulation of glucose homeostasis in both pre-diabetes and overt type 2 diabetes (T2D). However, the main clinical trials evaluating the efficacy of vitamin D supplementation for the control of glucose homeostasis in people at risk for or affected by T2D have yielded inconsistent results. The aim of this review is to summarize the rationale and results of randomized clinical trials testing vitamin D and its analogs in both autoimmune and T2D.
- Published
- 2018
20. Impact of chronic kidney disease on platelet reactivity and outcomes of patients receiving clopidogrel and undergoing percutaneous coronary intervention
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Germano Di Sciascio, Fabio Mangiacapra, Andrea D'Ambrosio, Ilaria Cavallari, Elisabetta Ricottini, Bernard De Bruyne, Emanuele Barbato, Giuseppe Patti, Vincenzo Vizzi, William Wijns, Mangiacapra, F, Cavallari, I, Barbato, Emanuele, Ricottini, E, Patti, G, Vizzi, V, D'Ambrosio, A, De Bruyne, B, Wijns, W, and Di Sciascio, G.
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Blood Platelets ,Male ,medicine.medical_specialty ,Ticlopidine ,Platelet Aggregation ,Platelet Function Tests ,medicine.medical_treatment ,Renal function ,Coronary Artery Disease ,Coronary artery disease ,Electrocardiography ,Percutaneous Coronary Intervention ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,Prospective Studies ,Renal Insufficiency, Chronic ,Prospective cohort study ,Aged ,business.industry ,Percutaneous coronary intervention ,Prognosis ,medicine.disease ,Clopidogrel ,Conventional PCI ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,business ,Platelet Aggregation Inhibitors ,Follow-Up Studies ,Glomerular Filtration Rate ,Kidney disease ,medicine.drug - Abstract
The impact of chronic kidney disease (CKD) on residual platelet reactivity (PR) in patients undergoing percutaneous coronary intervention (PCI) is still debatable. We sought to investigate the interaction between PR and renal function and the related clinical outcomes in patients with coronary artery disease treated with PCI. Immediately before PCI, we measured PR (as P2Y12 reaction units [PRUs]) in 800 patients on clopidogrel with the VerifyNow P2Y12 assay. High PR was defined as a PRU value of ≥240 and low PR as a PRU value of ≤178. Based on a glomerular filtration rate ofor ≥60 ml/min/1.73 m2, patients were respectively grouped into those with or without moderate-to-severe CKD. Primary end point was the incidence of 30-day net adverse clinical events (NACEs). Patients with moderate-to-severe CKD (n=173, 21.6%) and those without showed similar PRU values (208±67 vs 207±75, p=0.819). Yet, NACEs were significantly higher in patients with moderate-to-severe CKD (19.7% vs 9.1%, p0.001), in terms of both ischemic (12.1% vs 7.2%, p=0.036) and bleeding events (8.7% vs 2.1%, p0.001). NACEs were significantly higher when moderate-to-severe CKD was associated with either high PR or low PR (25.4%, p for trend0.001); this association was the strongest predictor of NACE at multivariate analysis (odds ratio 3.4, 95% confidence interval 2.0 to 5.6, p0.001). In conclusion, we did not find an association between moderate-to-severe CKD and residual PR on clopidogrel. However, the association of moderate-to-severe CKD with either high or low PR was a strong determinant of adverse events after PCI.
- Published
- 2014
21. Incretins-Based Therapies and Their Cardiovascular Effects: New Game-Changers for the Management of Patients with Diabetes and Cardiovascular Disease.
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Bernardini F, Nusca A, Coletti F, La Porta Y, Piscione M, Vespasiano F, Mangiacapra F, Ricottini E, Melfi R, Cavallari I, Ussia GP, and Grigioni F
- Abstract
Atherosclerosis is the leading cause of death worldwide, especially in patients with type 2 diabetes mellitus (T2D). GLP-1 receptor agonists and DPP-4 inhibitors were demonstrated to play a markedly protective role for the cardiovascular system beyond their glycemic control. Several cardiovascular outcome trials (CVOT) reported the association between using these agents and a significant reduction in cardiovascular events in patients with T2D and a high cardiovascular risk profile. Moreover, recent evidence highlights a favorable benefit/risk profile in myocardial infarction and percutaneous coronary revascularization settings. These clinical effects result from their actions on multiple molecular mechanisms involving the immune system, platelets, and endothelial and vascular smooth muscle cells. This comprehensive review specifically concentrates on these cellular and molecular processes mediating the cardiovascular effects of incretins-like molecules, aiming to improve clinicians' knowledge and stimulate a more extensive use of these drugs in clinical practice as helpful cardiovascular preventive strategies.
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- 2023
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22. Editorial: Moving beyond the molecular mechanisms of malignant pleural mesothelioma: Cues for novel biomarkers and drug targets.
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Cavallari I, Cerciello F, Giovannetti E, and Urso L
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Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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- 2023
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23. Repurposing Verapamil to Enhance Killing of T-ALL Cells by the mTOR Inhibitor Everolimus.
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Silic-Benussi M, Sharova E, Corradin A, Urso L, Raimondi V, Cavallari I, Buldini B, Francescato S, Minuzzo SA, D'Agostino DM, and Ciminale V
- Abstract
New therapies are needed for patients with T-cell lymphoblastic leukemia (T-ALL) who do not respond to standard chemotherapy. Our previous studies showed that the mTORC1 inhibitor everolimus increases reactive oxygen species (ROS) levels, decreases the levels of NADPH and glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP), and induces apoptosis in T-ALL cells. Studies in T-ALL-xenografted NOD/SCID mice demonstrated that everolimus improved their response to the glucocorticoid (GC) dexamethasone. Here we show that verapamil, a calcium antagonist used in the treatment of supraventricular tachyarrhythmias, enhanced the effects of everolimus on ROS and cell death in T-ALL cell lines. The death-enhancing effect was synergistic and was confirmed in assays on a panel of therapy-resistant patient-derived xenografts (PDX) and primary samples from T-ALL patients. The verapamil-everolimus combination produced a dramatic reduction in the levels of G6PD and induction of p38 MAPK phosphorylation. Studies of NOD/SCID mice inoculated with refractory T-ALL PDX cells demonstrated that the addition of verapamil to everolimus plus dexamethasone significantly reduced tumor growth in vivo. Taken together, our results provide a rationale for repurposing verapamil in association with mTORC inhibitors and GC to treat refractory T-ALL.
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- 2023
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24. mTOR inhibition downregulates glucose-6-phosphate dehydrogenase and induces ROS-dependent death in T-cell acute lymphoblastic leukemia cells.
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Silic-Benussi M, Sharova E, Ciccarese F, Cavallari I, Raimondi V, Urso L, Corradin A, Kotler H, Scattolin G, Buldini B, Francescato S, Basso G, Minuzzo SA, Indraccolo S, D'Agostino DM, and Ciminale V
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- Animals, Apoptosis, Cell Line, Tumor, Dexamethasone pharmacology, Dexamethasone therapeutic use, Everolimus pharmacology, Everolimus therapeutic use, Glucosephosphate Dehydrogenase genetics, Glucosephosphate Dehydrogenase metabolism, Humans, MTOR Inhibitors, Mice, Mice, Inbred NOD, Mice, SCID, NADP, Reactive Oxygen Species metabolism, T-Lymphocytes metabolism, TOR Serine-Threonine Kinases metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma metabolism
- Abstract
mTOR activation is a hallmark of T-cell acute lymphoblastic leukemia (T-ALL) and is associated with resistance to glucocorticoid (GC)-based chemotherapy. We previously showed that altering redox homeostasis primes T-ALL cells to GC-induced apoptosis. Here we investigated the connection between the mTOR pathway and redox homeostasis using pharmacological inhibitors and gene silencing. In vitro studies performed on T-ALL cell lines and CG-resistant patient-derived T-ALL xenograft (PDX) cells showed that the mTOR inhibitor everolimus increased reactive oxygen species (ROS) levels, augmented lipid peroxidation, and activated the ROS-controlled transcription factor NRF2. These effects were accompanied by a decrease in the levels of NADPH and of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP), which is a major source of cytosolic NADPH needed for maintaining the cellular ROS-scavenging capacity. The mTOR inhibitor everolimus induced mitochondrial inner membrane depolarization and dose-dependent apoptosis of T-ALL cells, but did not kill normal T-cells. Importantly, the combination of everolimus and the GC dexamethasone had a synergistic effect on killing T-ALL cells. The effects of mTOR inhibition were blunted by ROS scavengers and phenocopied by siRNA-mediated G6PD silencing. In vivo studies of NOD/SCID mice inoculated with refractory T-ALL PDX demonstrated that everolimus overcame dexamethasone resistance in conditions of high tumor burden that mimicked the clinical setting of acute leukemia. These findings provide insight into the crosstalk between mTOR and ROS homeostasis in T-ALL cells and furnish mechanistic evidence to support the combination of glucocorticoids with mTOR inhibitors as a therapeutic avenue for treating refractory T-ALL., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2022
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25. A Prospective Study to Evaluate the Effectiveness of Edoxaban for the Resolution of Left Atrial Thrombosis in Patients with Atrial Fibrillation.
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Patti G, Parato VM, Cavallari I, Calabrò P, Russo V, Renda G, Gragnano F, Pengo V, D'Onofrio A, Grimaldi M, and De Caterina R
- Abstract
Available evidence on left atrial (LA) thrombus dissolution in patients with atrial fibrillation (AF) largely refers to the use of vitamin K antagonist oral anticoagulants (VKAs), showing >50% thrombus resolution over a 4-week to 12-month treatment period. Available data on non-vitamin K antagonist anticoagulants (NOACs) in this setting are limited and derive from isolated case reports or observational small-sized investigations with dabigatran, rivaroxaban or apixaban. The aim of this study was to investigate the extent of thrombus resolution with edoxaban therapy in patients with AF and LA thrombosis. We conducted a prospective, observational, open-label pilot study in seven Italian institutions. We included a total of 25 patients with non-valvular AF and LA (or left atrial appendage (LAA)) thrombosis, documented by transesophageal echocardiography (TEE). All patients received edoxaban OD treatment (n = 23 on 60 mg daily; n = 2 on 30 mg daily) and underwent TEE examination after 4 weeks. The primary endpoint was the percentage of patients with complete thrombus resolution by TEE imaging at 4 weeks. The mean age of the study population was 68.3 ± 10.8 years with a female population of 16%. AF was permanent in all cases, with a mean arrhythmia duration of 4.3 ± 1.7 years. CHA2DS2-VASc and HAS-BLED scores were 3.2 ± 1.5 and 1.9 ± 1.1, respectively. We were able to demonstrate a complete thrombus resolution in 14 patients (56%) at 4 weeks. In patients with residual atrial thrombosis (n = 11), we observed a 15.4 ± 14.9% reduction in the thrombus area from baseline. As compared with patients without thrombus dissolution, those with thrombus resolution had a numerically lower-indexed LA diameter (27.9 ± 9.3 vs 34.8 ± 16.1 mm/m2), a smaller maximum thrombus area at baseline (45.5 ± 44.6 vs 63.9 ± 43.5 mm2), a higher left ventricular ejection fraction (47.4 ± 21.0% vs 38.4 ± 20.6%) and higher maximum LAA flow velocities (26.3 ± 15.2 vs 19.3 ± 10.0 cm/s). Figures on the percentage of thrombus resolution in this study are comparable to those reported in the literature for the other OACs. We conclude that, in patients with AF, the use of edoxaban is associated with a >50% resolution of atrial thrombus at 4 weeks, similar to studies using VKAs and the other NOACs (ClinicalTrials.gov identifier number: NCT034899395).
- Published
- 2022
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26. The miR-200 Family of microRNAs: Fine Tuners of Epithelial-Mesenchymal Transition and Circulating Cancer Biomarkers.
- Author
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Cavallari I, Ciccarese F, Sharova E, Urso L, Raimondi V, Silic-Benussi M, D'Agostino DM, and Ciminale V
- Abstract
The miR-200 family of microRNAs (miRNAs) includes miR-200a, miR-200b, miR-200c, miR-141 and miR-429, five evolutionarily conserved miRNAs that are encoded in two clusters of hairpin precursors located on human chromosome 1 (miR-200b, miR-200a and miR-429) and chromosome 12 (miR-200c and miR-141). The mature -3p products of the precursors are abundantly expressed in epithelial cells, where they contribute to maintaining the epithelial phenotype by repressing expression of factors that favor the process of epithelial-to-mesenchymal transition (EMT), a key hallmark of oncogenic transformation. Extensive studies of the expression and interactions of these miRNAs with cell signaling pathways indicate that they can exert both tumor suppressor- and pro-metastatic functions, and may serve as biomarkers of epithelial cancers. This review provides a summary of the role of miR-200 family members in EMT, factors that regulate their expression, and important targets for miR-200-mediated repression that are involved in EMT. The second part of the review discusses the potential utility of circulating miR-200 family members as diagnostic/prognostic biomarkers for breast, colorectal, lung, ovarian, prostate and bladder cancers.
- Published
- 2021
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27. Dual cytoplasmic and nuclear localization of HTLV-1-encoded HBZ protein is a unique feature of adult T-cell leukemia.
- Author
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Forlani G, Shallak M, Tedeschi A, Cavallari I, Marçais A, Hermine O, and Accolla RS
- Subjects
- Basic-Leucine Zipper Transcription Factors genetics, Cytoplasm, Gene Products, tax genetics, Humans, Retroviridae Proteins genetics, Viral Proteins, Human T-lymphotropic virus 1, Leukemia-Lymphoma, Adult T-Cell genetics
- Abstract
Adult T-cell leukemia-lymphoma (ATL), is a highly malignant T-cell neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1), characterized by a poor prognosis. Two viral proteins, Tax-1 and HBZ play important roles in the pathogenesis of ATL. While Tax-1 can be found in both cytoplasm and nucleus of HTLV-1 infected patients, HBZ is exclusively localized in the cytoplasm of HTLV-1 asymptomatic carriers and patients with chronic neurologic disease HAM/TSP, and only in the nucleus of ATL cell lines, suggesting that the nuclear localization of HBZ can be a hallmark of neoplastic transformation. To clarify this crucial point, here we investigated in detail the pattern of HBZ expression in ATL patients. We made use of our monoclonal antibody 4D4-F3, that at present is a uniquely reported reagent, among the few described, able to detect endogenous HBZ by immunofluorescence and confocal microscopy in cells from asymptomatic carriers, HAM/TSP and ATL patients. We found that HBZ localizes both in the cytoplasm and in the nucleus of cells of ATL patients irrespective of their clinical status, with a strong preference for the cytoplasmic localization. Also Tax-1 localized in both compartments. As HBZ is exclusively localized in the cytoplasm in asymptomatic carriers and in non-neoplastic pathologies, this finding shows that neoplastic transformation consequent to HTLV-1 infection is accompanied and associated with the capacity of HBZ to translocate to the nucleus, which suggests a role of cytoplasmic-to-nuclear translocation in HTLV-1-mediated oncogenesis.
- Published
- 2021
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28. Platelet Effects of Anti-diabetic Therapies: New Perspectives in the Management of Patients with Diabetes and Cardiovascular Disease.
- Author
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Nusca A, Tuccinardi D, Pieralice S, Giannone S, Carpenito M, Monte L, Watanabe M, Cavallari I, Maddaloni E, Ussia GP, Manfrini S, and Grigioni F
- Abstract
In type 2 diabetes, anti-thrombotic management is challenging, and current anti-platelet agents have demonstrated reduced efficacy. Old and new anti-diabetic drugs exhibited-besides lowering blood glucose levels-direct and indirect effects on platelet function and on thrombotic milieu, eventually conditioning cardiovascular outcomes. The present review summarizes existing evidence on the effects of glucose-lowering agents on platelet properties, addressing pre-clinical and clinical research, as well as drug-drug interactions with anti-platelet agents. We aimed at expanding clinicians' understanding by highlighting new opportunities for an optimal management of patients with diabetes and cardiovascular disease. We suggest how an improvement of the thrombotic risk in this large population of patients may be achieved by a careful and tailored combination of anti-diabetic and anti-platelet therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nusca, Tuccinardi, Pieralice, Giannone, Carpenito, Monte, Watanabe, Cavallari, Maddaloni, Ussia, Manfrini and Grigioni.)
- Published
- 2021
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29. Causes and Risk Factors for Death in Diabetes: A Competing-Risk Analysis From the SAVOR-TIMI 53 Trial.
- Author
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Cavallari I, Bhatt DL, Steg PG, Leiter LA, McGuire DK, Mosenzon O, Im K, Raz I, Braunwald E, and Scirica BM
- Subjects
- Adamantane administration & dosage, Adamantane adverse effects, Aged, Biomarkers blood, Cause of Death, Death, Sudden, Cardiac epidemiology, Dipeptidyl-Peptidase IV Inhibitors administration & dosage, Dipeptidyl-Peptidase IV Inhibitors adverse effects, Female, Heart Disease Risk Factors, Humans, Male, Mortality, Adamantane analogs & derivatives, Coronary Artery Disease complications, Coronary Artery Disease mortality, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 drug therapy, Dipeptides administration & dosage, Dipeptides adverse effects, Risk Assessment methods, Risk Assessment statistics & numerical data
- Published
- 2021
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30. Prognostic Stratification of Metastatic Prostate Cancer Patients Treated With Abiraterone and Enzalutamide Through an Integrated Analysis of Circulating Free microRNAs and Clinical Parameters.
- Author
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Sharova E, Maruzzo M, Del Bianco P, Cavallari I, Pierantoni F, Basso U, Ciminale V, and Zagonel V
- Abstract
Androgen Receptor-Targeted Agents (ARTA) have dramatically changed the therapeutic landscape of metastatic Castration-Resistant Prostate Cancer (mCRPC), but 20-40% of these patients progress early after start of ARTA treatment. The present study investigated the potential utility of plasma cell-free microRNAs (cfmiRNAs) as prognostic markers by analyzing a prospective cohort of 31 mCRCP patients treated with abiraterone ( N = 10) or enzalutamide ( N = 21). Additional potential prognostic factors were extracted from clinical records and outcome was evaluated as overall survival (OS) and progression-free survival (PFS). cfmiRNAs were measured in plasma samples using quantitative real-time RT-PCR. Linear correlation among clinical factors and cfmiRNAs was assessed using the Spearman's rank correlation coefficient. The association with survival was studied using univariate and multivariate Cox proportional hazards models. Continuous variables were dichotomized with the cut points corresponding to the most significant relation with the outcome. Univariate analysis indicated that plasma levels of miR-21-5p, miR-141-3p and miR-223-3p, time to development of castration-resistance (tCRPC), and blood hemoglobin (Hb) levels strongly correlated with both PFS and OS. Multivariate analysis revealed that low plasma levels of miR-21, shorter tCRPC, and lower Hb values were independent factors predicting reduced PFS and OS. These findings suggest that the integrated analysis of cfmiRNAs, tCRPC, and Hb may provide a promising, non-invasive tool for the prognostic stratification of mCRPC patients treated with ARTA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sharova, Maruzzo, Del Bianco, Cavallari, Pierantoni, Basso, Ciminale and Zagonel.)
- Published
- 2021
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31. Genetic Risk Score to Identify Risk of Venous Thromboembolism in Patients With Cardiometabolic Disease.
- Author
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Marston NA, Melloni GEM, Gurmu Y, Bonaca MP, Kamanu FK, Roselli C, Lee C, Cavallari I, Giugliano RP, Scirica BM, Bhatt DL, Steg PG, Cohen M, Storey RF, Keech AC, Raz I, Mosenzon O, Braunwald E, Lubitz SA, Ellinor PT, Sabatine MS, and Ruff CT
- Subjects
- Aged, Female, Humans, Male, Metabolic Syndrome pathology, Middle Aged, Proportional Hazards Models, Proprotein Convertase 9 genetics, Risk Factors, Venous Thromboembolism etiology, Metabolic Syndrome genetics, Venous Thromboembolism diagnosis
- Abstract
Background: Venous thromboembolism (VTE) is a major cause of cardiovascular morbidity and mortality and has a known genetic contribution. We tested the performance of a genetic risk score for its ability to predict VTE in 3 cohorts of patients with cardiometabolic disease., Methods: We included patients from the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus) trials (history of a major atherosclerotic cardiovascular event, myocardial infarction, and diabetes, respectively) who consented for genetic testing and were not on baseline anticoagulation. We calculated a VTE genetic risk score based on 297 single nucleotide polymorphisms with established genome-wide significance. Patients were divided into tertiles of genetic risk. Cox proportional hazards models were used to calculate hazard ratios for VTE across genetic risk groups. The polygenic risk score was compared with available clinical risk factors (age, obesity, smoking, history of heart failure, and diabetes) and common monogenic mutations., Results: A total of 29 663 patients were included in the analysis with a median follow-up of 2.4 years, of whom 174 had a VTE event. There was a significantly increased gradient of risk across VTE genetic risk tertiles ( P -trend <0.0001). After adjustment for clinical risk factors, patients in the intermediate and high genetic risk groups had a 1.88-fold (95% CI, 1.23-2.89; P =0.004) and 2.70-fold (95% CI, 1.81-4.06; P <0.0001) higher risk of VTE compared with patients with low genetic risk. In a continuous model adjusted for clinical risk factors, each standard deviation increase in the genetic risk score was associated with a 47% (95% CI, 29-68) increased risk of VTE ( P <0.0001)., Conclusions: In a broad spectrum of patients with cardiometabolic disease, a polygenic risk score is a strong, independent predictor of VTE after accounting for available clinical risk factors, identifying 1/3 of patients who have a risk of VTE comparable to that seen with established monogenic thrombophilia.
- Published
- 2021
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32. Early risk of mortality, cardiovascular events, and bleeding in patients with newly diagnosed atrial fibrillation.
- Author
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Cavallari I and Patti G
- Abstract
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is independently associated with a 1.5- to 2.0-fold higher risk of all-cause death and increased morbidity, in particular for heart failure and stroke. Previous studies have shown that the annual rate of death in AF patients is ∼5%; however, emerging data indicate that the risk of death, but also of thromboembolic and bleeding complications, is highest early after the diagnosis, especially during the first month. In light of these observations, patients with newly diagnosed AF deserve close monitoring and may benefit from a comprehensive care targeting modifiable risk factors for death, such as heart failure, diabetes, renal impairment, and vascular disease. Aim of this report is to focus on timing and causes of death as well as on temporal trends of cardiovascular and bleeding complications in patients with newly diagnosed AF., (Published on behalf of the European Society of Cardiology. © The Author(s) 2020.)
- Published
- 2020
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33. Prognostic Stratification of Bladder Cancer Patients with a MicroRNA-based Approach.
- Author
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Cavallari I, Grassi A, Del Bianco P, Aceti A, Zaborra C, Sharova E, Bertazzolo I, D'Agostino DM, Iafrate M, and Ciminale V
- Abstract
Robust non-invasive tests for prognostic stratification of bladder cancer (BCa) patients are in high demand. Following a comprehensive analysis of studies on BCa, we selected a panel of 29 microRNAs (miRNAs) and analyzed their levels in urine and plasma samples in a prospective cohort of 63 BCa patients (32 at high risk of recurrence and 31 low-risk cases) and 37 healthy controls using RT-qPCR. To design an assay suitable for large-scale testing, we applied a hierarchical pipeline to select the miRNAs that were not affected by confounding factors such as haematuria and urine specific gravity, and exceeded stringent cut-off criteria (fold change >2.5 and p- value < 0.005). Using a two-step decision tree based on the urine levels of miR-34a-5p, miR-200a-3p and miR-193a-5p, normalized against miR-125b-5p, patients could be classified as high- or low-risk with a sensitivity of 0.844, specificity of 0.806 and accuracy of 0.825. Furthermore, univariate Cox proportional hazards regression analyses indicated that increased urine levels of miR-29a-3p, miR-34a-5p, miR-193a-5p, miR-200c-3p, miR-205-5p and miR-532-5p were associated with a shorter event-free survival (hazard ratios > 3.1, p - value < 0.05). Taken together, our findings suggest that measuring the urine levels of these miRNAs could provide a novel cost-effective, noninvasive test for risk assessment of BCa patients.
- Published
- 2020
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34. Non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation and atrial thrombosis: An appraisal of current evidence.
- Author
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Calabrò P, Gragnano F, Cesaro A, Marsico F, Pariggiano I, Patti G, Moscarella E, Cavallari I, Sardu C, Parato VM, Renda G, Niccoli G, Marcucci R, and De Caterina R
- Subjects
- Administration, Oral, Antithrombins adverse effects, Atrial Fibrillation epidemiology, Atrial Fibrillation physiopathology, Evidence-Based Medicine, Factor Xa Inhibitors adverse effects, Hemorrhage chemically induced, Humans, Risk Factors, Stroke epidemiology, Stroke physiopathology, Thromboembolism epidemiology, Thromboembolism physiopathology, Thrombosis epidemiology, Thrombosis physiopathology, Treatment Outcome, Antithrombins administration & dosage, Atrial Fibrillation drug therapy, Factor Xa Inhibitors administration & dosage, Stroke prevention & control, Thromboembolism prevention & control, Thrombosis drug therapy
- Abstract
Major thromboembolic complications in patients with atrial fibrillation, secondary to thromboembolism from the left atrium or the left atrial appendage, are a major concern because of their burden of disabling stroke and mortality. To date, non-vitamin K antagonist oral anticoagulants (NOACs) are considered the first-line strategy in most patients with atrial fibrillation receiving chronic anticoagulation, as they have major advantages compared with vitamin K antagonists, including minimization of intracranial bleeding risk. Although several studies and post-hoc analyses have provided initial data on the use of NOACs in patients with documented atrial and/or left atrial appendage thrombosis, the benefit of NOACs in these patients has not been fully elucidated. In this review, we reappraise current evidence supporting the use of NOACs in patients with established atrial and/or left atrial appendage thrombosis, discussing potential mechanisms favouring the use of a NOAC-based strategy in this special setting., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
- Published
- 2020
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35. The Vicious Circle of Left Ventricular Dysfunction and Diabetes: From Pathophysiology to Emerging Treatments.
- Author
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Cavallari I, Maddaloni E, Pieralice S, Mulè MT, Buzzetti R, Ussia GP, Pozzilli P, and Grigioni F
- Subjects
- Cardiology methods, Cardiology trends, Endocrinology methods, Endocrinology trends, Heart Failure diagnosis, Heart Failure epidemiology, Heart Failure etiology, Heart Failure therapy, Humans, Therapies, Investigational methods, Diabetes Mellitus diagnosis, Diabetes Mellitus epidemiology, Diabetes Mellitus therapy, Diabetic Angiopathies diagnosis, Diabetic Angiopathies epidemiology, Diabetic Angiopathies therapy, Therapies, Investigational trends, Ventricular Dysfunction, Left diagnosis, Ventricular Dysfunction, Left epidemiology, Ventricular Dysfunction, Left etiology, Ventricular Dysfunction, Left therapy
- Abstract
Context: Diabetes and heart failure (HF) are 2 deadly and strictly related epidemic disorders. The aim of this review is to present an updated discussion of the epidemiology, pathophysiology, clinical presentation and treatment options for HF in diabetes., Evidence Acquisition: Relevant references published up to February 2020 were identified through searches in PubMed. Quality was graded using the Newcastle-Ottawa score in observational studies and the Cochrane Collaboration tool in randomized studies., Evidence Synthesis: Metabolic and neurohumoral derangements, oxidative stress, inflammation, micro- and macroangiopathy all contribute through complex molecular and cellular mechanisms to cardiac dysfunction in diabetes, which in turn, results as one the most frequent underlying conditions affecting up to 42% of patients with HF and causing a 34% increased risk of cardiovascular death. On top of traditional guideline-based HF medical and device therapies, equally effective in patients with and without diabetes, a new class of glucose-lowering agents acting through the sodium-glucose cotransporter 2 (SGLT2) inhibition showed impressive results in reducing HF outcomes in individuals with diabetes and represents an active area of investigation., Conclusions: Diabetes and HF are strictly linked in a bidirectional and deadly vicious circle difficult to break. Therefore, preventive strategies and a timely diagnosis are crucial to improve outcomes in such patients. SGLT2 inhibitors represent a major breakthrough with remarkably consistent findings. However, it is still not clear whether their benefits may be definitely extended to patients with HF with preserved ejection fraction, to those without diabetes and in the acute setting., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2020
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36. Metabolic rewiring and redox alterations in malignant pleural mesothelioma.
- Author
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Urso L, Cavallari I, Sharova E, Ciccarese F, Pasello G, and Ciminale V
- Subjects
- Animals, Antineoplastic Agents therapeutic use, Asbestos adverse effects, Cell Transformation, Neoplastic metabolism, Cisplatin therapeutic use, Humans, Loss of Function Mutation, Lung Neoplasms drug therapy, Lung Neoplasms etiology, Mesothelioma drug therapy, Mesothelioma etiology, Mesothelioma, Malignant, Oxidation-Reduction, Pleural Neoplasms drug therapy, Pleural Neoplasms etiology, Reactive Oxygen Species metabolism, Transforming Growth Factor beta, Transforming Growth Factor beta1 metabolism, Tumor Suppressor Proteins genetics, Ubiquitin Thiolesterase genetics, Lung Neoplasms genetics, Lung Neoplasms metabolism, Mesothelioma genetics, Mesothelioma metabolism, Pleural Neoplasms genetics, Pleural Neoplasms metabolism
- Abstract
Malignant pleural mesothelioma (MPM) is a rare malignancy of mesothelial cells with increasing incidence, and in many cases, dismal prognosis due to its aggressiveness and lack of effective therapies. Environmental and occupational exposure to asbestos is considered the main aetiological factor for MPM. Inhaled asbestos fibres accumulate in the lungs and induce the generation of reactive oxygen species (ROS) due to the presence of iron associated with the fibrous silicates and to the activation of macrophages and inflammation. Chronic inflammation and a ROS-enriched microenvironment can foster the malignant transformation of mesothelial cells. In addition, MPM cells have a highly glycolytic metabolic profile and are positive in
18 F-FDG PET analysis. Loss-of-function mutations of BRCA-associated protein 1 (BAP1) are a major contributor to the metabolic rewiring of MPM cells. A subset of MPM tumours show loss of the methyladenosine phosphorylase (MTAP) locus, resulting in profound alterations in polyamine metabolism, ATP and methionine salvage pathways, as well as changes in epigenetic control of gene expression. This review provides an overview of the perturbations in metabolism and ROS homoeostasis of MPM cells and the role of these alterations in malignant transformation and tumour progression.- Published
- 2020
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37. Liquid Biopsy in Malignant Pleural Mesothelioma: State of the Art, Pitfalls, and Perspectives.
- Author
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Cavallari I, Urso L, Sharova E, Pasello G, and Ciminale V
- Abstract
Malignant pleural mesothelioma (MPM) is an aggressive tumor linked to asbestos exposure. Although the risk factors for MPM are well-known, the majority of MPM patients are diagnosed at an advanced stage and have a very poor prognosis. Circulating biomarkers for early diagnosis remain to be identified, and the current standard for MPM diagnosis relies on pleural biopsies. Robust non-invasive tests for the screening of asbestos-exposed subjects are therefore an important unmet clinical need. This review provides a critical summary of recent liquid biopsy-based studies aimed at discovering novel blood-based circulating biomarkers for the early diagnosis and prognostic stratification of MPM patients.
- Published
- 2019
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38. Selective killing of human T-ALL cells: an integrated approach targeting redox homeostasis and the OMA1/OPA1 axis.
- Author
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Silic-Benussi M, Scattolin G, Cavallari I, Minuzzo S, Del Bianco P, Francescato S, Basso G, Indraccolo S, D'Agostino DM, and Ciminale V
- Subjects
- Animals, Apoptosis drug effects, Benzimidazoles chemistry, Benzimidazoles pharmacology, Benzimidazoles therapeutic use, Dehydroepiandrosterone pharmacology, Dehydroepiandrosterone therapeutic use, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Mitochondria metabolism, Mitochondria pathology, Mitochondrial Proteins metabolism, NF-E2-Related Factor 2 metabolism, Oxidation-Reduction, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology, Reactive Oxygen Species chemistry, Reactive Oxygen Species metabolism, T-Lymphocytes cytology, T-Lymphocytes drug effects, T-Lymphocytes metabolism, TNF-Related Apoptosis-Inducing Ligand pharmacology, Transplantation, Heterologous, GTP Phosphohydrolases metabolism, Metalloendopeptidases metabolism
- Abstract
Approximately 20% of pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients are currently incurable due to primary or secondary resistance to glucocorticoid-based therapies. Here we employed an integrated approach to selectively kill T-ALL cells by increasing mitochondrial reactive oxygen species (ROS) using NS1619, a benzimidazolone that activates the K
+ (BK) channel, and dehydroepiandrosterone (DHEA), which blunts ROS scavenging through inhibition of the pentose phosphate pathway. These compounds selectively killed T-ALL cell lines, patient-derived xenografts and primary cells from patients with refractory T-ALL, but did not kill normal human thymocytes. T-ALL cells treated with NS1619 and DHEA showed activation of the ROS-responsive transcription factor NRF2, indicating engagement of antioxidant pathways, as well as increased cleavage of OPA1, a mitochondrial protein that promotes mitochondrial fusion and regulates apoptosis. Consistent with these observations, transmission electron microscopy analysis indicated that NS1619 and DHEA increased mitochondrial fission. OPA1 cleavage and cell death were inhibited by ROS scavengers and by siRNA-mediated knockdown of the mitochondrial protease OMA1, indicating the engagement of a ROS-OMA1-OPA1 axis in T-ALL cells. Furthermore, NS1619 and DHEA sensitized T-ALL cells to TRAIL-induced apoptosis. In vivo, the combination of dexamethasone and NS1619 significantly reduced the growth of a glucocorticoid-resistant patient-derived T-ALL xenograft. Taken together, our findings provide proof-of-principle for an integrated ROS-based pharmacological approach to target refractory T-ALL.- Published
- 2018
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39. A Preclinical Model for the ATLL Lymphoma Subtype With Insights Into the Role of Microenvironment in HTLV-1-Mediated Lymphomagenesis.
- Author
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Vicario M, Mattiolo A, Montini B, Piano MA, Cavallari I, Amadori A, Chieco-Bianchi L, and Calabrò ML
- Abstract
Adult T cell Leukemia/Lymphoma (ATLL) is a mature T cell malignancy associated with Human T cell Leukemia Virus type 1 (HTLV-1) infection. Among its four main clinical subtypes, the prognosis of acute and lymphoma variants remains poor. The long latency (3-6 decades) and low incidence (3-5%) of ATLL imply the involvement of viral and host factors in full-blown malignancy. Despite multiple preclinical and clinical studies, the contribution of the stromal microenvironment in ATLL development is not yet completely unraveled. The aims of this study were to investigate the role of the host microenvironment, and specifically fibroblasts, in ATLL pathogenesis and to propose a murine model for the lymphoma subtype. Here we present evidence that the oncogenic capacity of HTLV-1-immortalized C91/PL cells is enhanced when they are xenotransplanted together with human foreskin fibroblasts (HFF) in immunocompromised BALB/c Rag2
-/- γc -/- mice. Moreover, cell lines derived from a developed lymphoma and their subsequent in vivo passages acquired the stable property to induce aggressive T cell lymphomas. In particular, one of these cell lines, C91/III cells, consistently induced aggressive lymphomas also in NOD/SCID/IL2Rγc KO (NSG) mice. To dissect the mechanisms linked to this enhanced tumorigenic ability, we quantified 45 soluble factors released by these cell lines and found that 21 of them, mainly pro-inflammatory cytokines and chemokines, were significantly increased in C91/III cells compared to the parental C91/PL cells. Moreover, many of the increased factors were also released by human fibroblasts and belonged to the known secretory pattern of ATLL cells. C91/PL cells co-cultured with HFF showed features reminiscent of those observed in C91/III cells, including a similar secretory pattern and a more aggressive behavior in vivo . On the whole, our data provide evidence that fibroblasts, one of the major stromal components, might enhance tumorigenesis of HTLV-1-infected and immortalized T cells, thus throwing light on the role of microenvironment contribution in ATLL pathogenesis. We also propose that the lymphoma induced in NSG mice by injection with C91/III cells represents a new murine preclinical ATLL model that could be adopted to test novel therapeutic interventions for the aggressive lymphoma subtype.- Published
- 2018
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40. Expression of miR-34a in T-Cells Infected by Human T-Lymphotropic Virus 1.
- Author
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Sharma VK, Raimondi V, Ruggero K, Pise-Masison CA, Cavallari I, Silic-Benussi M, Ciminale V, and D'Agostino DM
- Abstract
Human T-lymphotropic virus 1 (HTLV-1) immortalizes T-cells and is the causative agent of adult T-cell leukemia/lymphoma (ATLL). HTLV-1 replication and transformation are governed by multiple interactions between viral regulatory proteins and host cell factors that remain to be fully elucidated. The present study investigated the impact of HTLV-1 infection on the expression of miR-34a, a microRNA whose expression is downregulated in many types of cancer. Results of RT-PCR assays showed that five out of six HTLV-1-positive cell lines expressed higher levels of miR-34a compared to normal PBMC or purified CD4+ T-cells. ATLL cell line ED, which did not express miR-34a, showed methylation of the miR-34a promoter. Newly infected PBMC and samples from 10 ATLL patients also showed a prominent increase in miR-34a expression compared to PBMC controls. The primary miR-34a transcript expressed in infected cell line C91PL contained binding motifs for NF-κB and p53. Pharmacological inhibition of NF-κB with Bay 11-7082 indicated that this pathway contributes to sustain miR-34a levels in infected cells. Treatment of infected cell lines with the p53 activator nutlin-3a resulted in a further increase in miR-34a levels, thus confirming it as a transcriptional target of p53. Nutlin-3a-treated cells showed downregulation of known miR-34a targets including the deacetylase SIRT1, which was accompanied by increased acetylation of p53, a substrate of SIRT1. Transfection of C91PL cells with a miR-34a mimic also led to downregulation of mRNA targets including SIRT1 as well as the pro-apoptotic factor BAX. Unlike nutlin-3a, the miR-34a mimic did not cause cell cycle arrest or reduce cell viability. On the other hand, sequestration of miR-34a with a sponge construct resulted in an increase in death of C91PL cells. These findings provide evidence for a functional role for miR-34a in fine-tuning the expression of target genes that influence the turnover of HTLV-1-infected cells.
- Published
- 2018
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41. Author`s Reply.
- Author
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Cavallari I and Patti G
- Subjects
- Heart, Humans, Atrial Fibrillation, Fibrinolytic Agents
- Published
- 2018
42. Frequency, Predictors, and Impact of Combined Antiplatelet Therapy on Venous Thromboembolism in Patients With Symptomatic Atherosclerosis.
- Author
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Cavallari I, Morrow DA, Creager MA, Olin J, Bhatt DL, Steg PG, Storey RF, Cohen M, Scirica BS, Piazza G, Goodrich EL, Braunwald E, Sabatine MS, and Bonaca MP
- Subjects
- Aged, Drug Therapy, Combination, Female, Humans, Male, Middle Aged, Myocardial Infarction drug therapy, Myocardial Infarction epidemiology, Myocardial Infarction physiopathology, Risk Factors, Aspirin administration & dosage, Atherosclerosis drug therapy, Atherosclerosis epidemiology, Atherosclerosis physiopathology, Platelet Aggregation Inhibitors administration & dosage, Ticagrelor administration & dosage, Venous Thromboembolism drug therapy, Venous Thromboembolism epidemiology, Venous Thromboembolism physiopathology
- Abstract
Background: Observational studies suggest that symptomatic atherosclerosis may be associated with risk of venous thromboembolism (VTE). Prior randomized studies have demonstrated a significant reduction in recurrent VTE with aspirin monotherapy. Whether VTE risk is associated with more severe symptomatic atherosclerosis and more intensive antiplatelet therapy reduces VTE risk beyond aspirin monotherapy is unknown., Methods: TRA2P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction) (vorapaxar) and PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) (ticagrelor) were blinded, randomized placebo-controlled trials of antiplatelet therapy for the prevention of ischemic events in stable patients with symptomatic atherosclerosis. Two blinded vascular specialists systematically identified symptomatic venous thromboembolic events in both trials., Results: Of 47 611 patients with stable vascular disease followed for 3 years in both studies there were 343 VTE events in 301 patients (Kaplan-Meier rate at 3 years, 0.9% for placebo). The risk of VTE was independently associated with age, body mass index, polyvascular disease, chronic obstructive pulmonary disease, and malignancy. The burden of atherosclerosis manifested as an increasing number of symptomatic vascular territories was associated with a graded increase in the 3-year rates of VTE (0.76% for 1, 1.53% for 2, and 2.45% for 3 territories). More intensive antiplatelet therapy (vorapaxar and ticagrelor pooled) significantly reduced the risk of VTE by 29% compared with background antiplatelet therapy, from 0.93% to 0.64% at 3 years (hazard ratio, 0.71; 95% confidence interval, 0.56-0.89; P =0.003)., Conclusions: The rate of VTE in patients with atherosclerosis is ≈0.3% per year while on treatment with ≥1 antiplatelet agent, with increased risk independently associated with the number of symptomatic vascular territories. More intensive antiplatelet therapy reduces the risk of VTE. These data suggest a relationship between atherosclerosis burden and VTE risk, and they support inclusion of VTE as a prospective end point in long-term secondary prevention trials evaluating the risks and benefits of antiplatelet therapies in patients with atherosclerosis., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01225562., (© 2017 American Heart Association, Inc.)
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- 2018
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43. Mitochondrial Proteins Coded by Human Tumor Viruses.
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Cavallari I, Scattolin G, Silic-Benussi M, Raimondi V, D'Agostino DM, and Ciminale V
- Abstract
Viruses must exploit the cellular biosynthetic machinery and evade cellular defense systems to complete their life cycles. Due to their crucial roles in cellular bioenergetics, apoptosis, innate immunity and redox balance, mitochondria are important functional targets of many viruses, including tumor viruses. The present review describes the interactions between mitochondria and proteins coded by the human tumor viruses human T-cell leukemia virus type 1, Epstein-Barr virus, Kaposi's sarcoma-associated herpesvirus, human hepatitis viruses B and C, and human papillomavirus, and highlights how these interactions contribute to viral replication, persistence and transformation.
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- 2018
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44. Efficacy and safety of oral anticoagulation in elderly patients with atrial fibrillation.
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Cavallari I and Patti G
- Subjects
- Aged, Anticoagulants adverse effects, Health Services for the Aged, Hemorrhage chemically induced, Humans, Patient Safety, Thromboembolism chemically induced, Warfarin adverse effects, Anticoagulants therapeutic use, Atrial Fibrillation, Stroke prevention & control, Warfarin therapeutic use
- Abstract
Elderly patients with atrial fibrillation are at a higher risk of both ischemic and bleeding events compared with younger patients; therefore, balancing risks and benefits of antithrombotic strategies in this population is crucial. Recent studies have shown that because the risk of stroke increases with age more than the risk of bleeding, the absolute benefit of oral anticoagulation is the highest in elderly patients in whom it outweighs the risk of bleeding. Direct oral anticoagulants (DOACs) have been developed as a treatment for the prevention of cardioembolic stroke to overcome some limitations of warfarin, such as the need for frequent monitoring, labile INR values requiring frequent dose adjustment, dietary and drugs interactions, and increased risk of intracranial bleeding. Despite the better safety profiles of DOACs compared with warfarin, elderly patients often remain undertreated because of the fear of bleeding complications. This review summarizes current evidence regarding the risks of thromboembolisms and bleeding in different antithrombotic strategies in elderly patients (aged ≥75 years) with atrial fibrillation, including data from the warfarin-controlled phase 3 DOACs trials.
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- 2018
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45. Prevalence and predictors of dual antiplatelet therapy prolongation beyond one year in patients with acute coronary syndrome.
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Patti G, Cavallari I, Antonucci E, Calabrò P, Cirillo P, Gresele P, Palareti G, Pengo V, Pignatelli P, Ricottini E, and Marcucci R
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- Aged, Drug Administration Schedule, Female, Humans, Italy, Male, Middle Aged, Platelet Aggregation Inhibitors administration & dosage, Registries, Acute Coronary Syndrome drug therapy, Platelet Aggregation Inhibitors therapeutic use
- Abstract
There are limited real-world data on prevalence and predictors of dual antiplatelet therapy (DAPT) prolongation beyond one year after acute coronary syndrome (ACS). We have explored such issue in the START ANTIPLATELET Registry, which is a prospective, observational, multicenter, Italian registry performed in seven Italian cardiology institutions including patients admitted for ACS and followed up to one year. Out of a total population of 840 ACS patients, 596 patients had completed 12-month follow-up being on DAPT. Decision to prolong DAPT beyond one year was taken in 79 patients (13%), whereas in 517 patients DAPT was stopped. The strongest predictors of DAPT continuation were a new cardiovascular events after the index admission event (OR 3.3, 95% CI 1.4-7.7), no bleeding complications (OR 3.2, 95% CI 1.2-8.3) and no anemia during one-year follow-up (OR 2.6, 95% CI 1.1-5.9); other independent predictors were renal failure (OR 2.5, 95% CI 1.3-5.0) and peripheral artery disease (OR 1.8, 95% CI 1.1-3.0). The choice of DAPT prolongation was not correlated with younger ager, presence of diabetes mellitus, coronary angioplasty as initial treatment strategy or type of implanted stent (drug-eluting vs bare metal). In conclusion, this study provides a real-world snapshot on the factors influencing the option to continue DAPT beyond one year after ACS; a low bleeding risk seems to influence the choice to prolong DAPT more than a high ischemic risk.
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- 2017
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46. Thromboembolic Risk, Bleeding Outcomes and Effect of Different Antithrombotic Strategies in Very Elderly Patients With Atrial Fibrillation: A Sub-Analysis From the PREFER in AF ( PRE vention o F Thromboembolic Events- E uropean R egistry in A trial F ibrillation).
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Patti G, Lucerna M, Pecen L, Siller-Matula JM, Cavallari I, Kirchhof P, and De Caterina R
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- Administration, Oral, Age Factors, Aged, Aged, 80 and over, Anticoagulants administration & dosage, Atrial Fibrillation complications, Atrial Fibrillation diagnosis, Atrial Fibrillation mortality, Clinical Decision-Making, Europe, Female, Fibrinolytic Agents administration & dosage, Hemorrhage mortality, Humans, Incidence, Ischemic Attack, Transient diagnosis, Ischemic Attack, Transient etiology, Ischemic Attack, Transient mortality, Male, Patient Selection, Platelet Aggregation Inhibitors administration & dosage, Registries, Risk Assessment, Risk Factors, Stroke diagnosis, Stroke etiology, Stroke mortality, Thromboembolism diagnosis, Thromboembolism etiology, Thromboembolism mortality, Time Factors, Treatment Outcome, Anticoagulants adverse effects, Atrial Fibrillation drug therapy, Fibrinolytic Agents adverse effects, Hemorrhage chemically induced, Ischemic Attack, Transient prevention & control, Platelet Aggregation Inhibitors adverse effects, Stroke prevention & control, Thromboembolism prevention & control
- Abstract
Background: Increasing age predisposes to both thromboembolic and bleeding events in patients with atrial fibrillation; therefore, balancing risks and benefits of antithrombotic strategies in older populations is crucial. We investigated 1-year outcome with different antithrombotic approaches in very elderly atrial fibrillation patients (age ≥85 years) compared with younger patients., Methods and Results: We accessed individual patients' data from the prospective PREFER in AF (PREvention oF thromboembolic events-European Registry in Atrial Fibrillation), compared outcomes with and without oral anticoagulation (OAC), and estimated weighed net clinical benefit in different age groups. A total of 6412 patients, 505 of whom were aged ≥85 years, were analyzed. In patients aged <85 years, the incidence of thromboembolic events was 2.8%/year without OAC versus 2.3%/year with OAC (0.5% absolute reduction); in patients aged ≥85 years, it was 6.3%/year versus 4.3%/year (2% absolute reduction). In very elderly patients, the risk of major bleeding was higher than in younger patients, but similar in patients on OAC and in those on antiplatelet therapy or without antithrombotic treatment (4.0%/year versus 4.2%/year; P =0.77). OAC was overall associated with weighted net clinical benefit, assigning weights to nonfatal events according to their prognostic implication for subsequent death (-2.19%; CI, -4.23%, -0.15%; P =0.036). We found a significant gradient of this benefit as a function of age, with the oldest patients deriving the highest benefit., Conclusions: Because the risk of stroke increases with age more than the risk of bleeding, the absolute benefit of OAC is highest in very elderly patients, where it, by far, outweighs the risk of bleeding, with the greatest net clinical benefit in such patients., (© 2017 The Authors and Daiichi Sankyo Europe GmbH. Published on behalf of the American Heart Association, Inc., by Wiley.)
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- 2017
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47. Synergistic targeting of malignant pleural mesothelioma cells by MDM2 inhibitors and TRAIL agonists.
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Urso L, Cavallari I, Silic-Benussi M, Biasini L, Zago G, Calabrese F, Conte PF, Ciminale V, and Pasello G
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- Animals, Apoptosis drug effects, Biomarkers, Tumor, Cell Cycle Checkpoints genetics, Cell Line, Tumor, Drug Synergism, Humans, Imidazoles metabolism, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology, Mesothelioma drug therapy, Mesothelioma genetics, Mesothelioma pathology, Mesothelioma, Malignant, Mice, Mutation, Piperazines metabolism, Pleural Neoplasms drug therapy, Pleural Neoplasms genetics, Pleural Neoplasms pathology, TNF-Related Apoptosis-Inducing Ligand pharmacology, Antineoplastic Agents pharmacology, Lung Neoplasms metabolism, Mesothelioma metabolism, Pleural Neoplasms metabolism, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-mdm2 metabolism, TNF-Related Apoptosis-Inducing Ligand agonists
- Abstract
Malignant Pleural Mesothelioma (MPM) is a chemoresistant tumor characterized by low rate of p53 mutation and upregulation of Murine Double Minute 2 (MDM2), suggesting that it may be effectively targeted using MDM2 inhibitors. In the present study, we investigated the anticancer activity of the MDM2 inhibitors Nutlin 3a (in vitro) and RG7112 (in vivo), as single agents or in combination with rhTRAIL.In vitro studies were performed using MPM cell lines derived from epithelioid (ZL55, M14K), biphasic (MSTO211H) and sarcomatoid (ZL34) MPMs. In vivo studies were conducted on a sarcomatoid MPM mouse model.In all the cell lines tested (with the exception of ZL55, which carries a biallelic loss-of-function mutation of p53), Nutlin 3a enhanced p21, MDM2 and DR5 expression, and decreased survivin expression. These changes were associated to cell cycle arrest but not to a significant induction of apoptosis. A synergistic pro-apoptotic effect was obtained through the association of rhTRAIL in all the cell lines harboring functional p53. This synergistic interaction of MDM2 inhibitor and TRAIL agonist was confirmed using a mouse preclinical model. Our results suggest that the combined targeting of MDM2 and TRAIL might provide a novel therapeutic option for treatment of MPM patients, particularly in the case of sarcomatoid MPM with MDM2 overexpression and functional inactivation of wild-type p53.
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- 2017
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48. The left atrial appendage: from embryology to prevention of thromboembolism.
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Patti G, Pengo V, Marcucci R, Cirillo P, Renda G, Santilli F, Calabrò P, De Caterina AR, Cavallari I, Ricottini E, Parato VM, Zoppellaro G, Di Gioia G, Sedati P, Cicchitti V, Davì G, Golia E, Pariggiano I, Simeone P, Abbate R, Prisco D, Zimarino M, Sofi F, Andreotti F, and De Caterina R
- Subjects
- Atrial Appendage anatomy & histology, Atrial Appendage embryology, Atrial Appendage physiology, Atrial Fibrillation complications, Blood Flow Velocity physiology, Echocardiography, Endothelium, Vascular physiology, Humans, Magnetic Resonance Angiography, Septal Occluder Device, Stroke prevention & control, Therapeutic Occlusion instrumentation, Therapeutic Occlusion methods, Thromboembolism etiology, Tomography, X-Ray Computed, Thromboembolism prevention & control
- Abstract
The left atrial appendage (LAA) is the main source of thromboembolism in patients with non-valvular atrial fibrillation (AF). As such, the LAA can be the target of specific occluding device therapies. Optimal management of patients with AF includes a comprehensive knowledge of the many aspects related to LAA structure and thrombosis. Here we provide baseline notions on the anatomy and function of the LAA, and then focus on current imaging tools for the identification of anatomical varieties. We also describe pathogenetic mechanisms of LAA thrombosis in AF patients, and examine the available evidence on treatment strategies for LAA thrombosis, including the use of non-vitamin K antagonist oral anticoagulants and interventional approaches., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)
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- 2017
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49. Insulin-Requiring Versus Noninsulin-Requiring Diabetes and Thromboembolic Risk in Patients With Atrial Fibrillation: PREFER in AF.
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Patti G, Lucerna M, Cavallari I, Ricottini E, Renda G, Pecen L, Romeo F, Le Heuzey JY, Zamorano JL, Kirchhof P, and De Caterina R
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- Aged, Atrial Fibrillation, Female, Humans, Male, Prospective Studies, Risk Factors, Thromboembolism prevention & control, Diabetes Complications, Diabetes Mellitus, Type 1 complications, Insulin therapeutic use, Thromboembolism etiology
- Abstract
Background: Diabetes is a known risk predictor for thromboembolic events in patients with atrial fibrillation (AF), but no study has explored the prognostic weight of insulin in this setting., Objectives: This study evaluated the differential role of insulin versus no insulin therapy on thromboembolic risk in patients with diabetes and AF., Methods: We accessed individual patient data from the prospective, real-world, multicenter, PREFER in AF (European Prevention of thromboembolic events-European Registry in Atrial Fibrillation). We compared the rates of stroke/systemic embolism at 1 year according to diabetes status (no diabetes, diabetes without insulin therapy, diabetes on insulin therapy)., Results: In an overall population of 5,717 patients, 1,288 had diabetes, 22.4% of whom were on insulin. For patients with diabetes who were on insulin, there was a significantly increased risk of stroke/systemic embolism at 1 year versus either no diabetes (5.2% vs. 1.9%; hazard ratio: 2.89; 95% confidence interval: 1.67 to 5.02; p = 0.0002) or diabetes without insulin treatment (5.2% vs. 1.8%; hazard ratio: 2.96; 95% confidence interval: 1.49 to 5.87; p = 0.0019). Notably, rates of stroke/embolism were similar in patients with diabetes not receiving insulin versus patients without diabetes (hazard ratio: 0.97; 95% confidence interval: 0.58 to 1.61; p = 0.90). The selective predictive role of insulin-requiring diabetes was independent of potential confounders, including diabetes duration, and was maintained in various subpopulations, including the subgroup receiving anticoagulant therapy., Conclusions: In this cohort of anticoagulated patients with AF, the sole presence of diabetes not requiring insulin did not imply an increased thromboembolic risk. Conversely, insulin-requiring diabetes contributed most, if not exclusively, to the overall increase of thromboembolic risk in AF., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
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- 2017
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50. Expression of Alternatively Spliced Human T-Cell Leukemia Virus Type 1 mRNAs Is Influenced by Mitosis and by a Novel cis-Acting Regulatory Sequence.
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Cavallari I, Rende F, Bona MK, Sztuba-Solinska J, Silic-Benussi M, Tognon M, LeGrice SF, Franchini G, D'Agostino DM, and Ciminale V
- Subjects
- Gene Expression, Gene Expression Profiling, Gene Knockout Techniques, Gene Products, rex deficiency, Gene Products, rex genetics, HeLa Cells, Humans, RNA, Messenger genetics, RNA, Viral genetics, Regulatory Sequences, Ribonucleic Acid, Gene Expression Regulation, Viral, Host-Pathogen Interactions, Human T-lymphotropic virus 1 genetics, Mitosis, RNA Splicing, RNA, Messenger metabolism, RNA, Viral metabolism
- Abstract
Unlabelled: Human T-cell leukemia virus type 1 (HTLV-1) expression depends on the concerted action of Tax, which drives transcription of the viral genome, and Rex, which favors expression of incompletely spliced mRNAs and determines a 2-phase temporal pattern of viral expression. In the present study, we investigated the Rex dependence of the complete set of alternatively spliced HTLV-1 mRNAs. Analyses of cells transfected with Rex-wild-type and Rex-knockout HTLV-1 molecular clones using splice site-specific quantitative reverse transcription (qRT)-PCR revealed that mRNAs encoding the p30Tof, p13, and p12/8 proteins were Rex dependent, while the p21rex mRNA was Rex independent. These findings provide a rational explanation for the intermediate-late temporal pattern of expression of the p30tof, p13, and p12/8 mRNAs described in previous studies. All the Rex-dependent mRNAs contained a 75-nucleotide intronic region that increased the nuclear retention and degradation of a reporter mRNA in the absence of other viral sequences. Selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) analysis revealed that this sequence formed a stable hairpin structure. Cell cycle synchronization experiments indicated that mitosis partially bypasses the requirement for Rex to export Rex-dependent HTLV-1 transcripts. These findings indicate a link between the cycling properties of the host cell and the temporal pattern of viral expression/latency that might influence the ability of the virus to spread and evade the immune system., Importance: HTLV-1 is a complex retrovirus that causes two distinct pathologies termed adult T-cell leukemia/lymphoma and tropical spastic paraparesis/HTLV-1-associated myelopathy in about 5% of infected individuals. Expression of the virus depends on the concerted action of Tax, which drives transcription of the viral genome, and Rex, which favors expression of incompletely spliced mRNAs and determines a 2-phase temporal pattern of virus expression. The findings reported in this study revealed a novel cis-acting regulatory element and indicated that mitosis partially bypasses the requirement for Rex to export Rex-dependent HTLV-1 transcripts. Our results add a layer of complexity to the mechanisms controlling the expression of alternatively spliced HTLV-1 mRNAs and suggest a link between the cycling properties of the host cell and the temporal pattern of viral expression/latency that might influence the ability of the virus to spread and evade the immune system., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
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