36 results on '"Salvatore Nicola Bertuccio"'
Search Results
2. Neuronopathic Gaucher disease models reveal defects in cell growth promoted by Hippo pathway activation
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Daria Messelodi, Silvia Strocchi, Salvatore Nicola Bertuccio, Pascale Baden, Valentina Indio, Federico M. Giorgi, Alberto Taddia, Salvatore Serravalle, Sabrina Valente, Alessio di Fonzo, Emanuele Frattini, Roberto Bernardoni, Annalisa Pession, Daniela Grifoni, Michela Deleidi, Annalisa Astolfi, and Andrea Pession
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Biology (General) ,QH301-705.5 - Abstract
Abstract Gaucher Disease (GD), the most common lysosomal disorder, arises from mutations in the GBA1 gene and is characterized by a wide spectrum of phenotypes, ranging from mild hematological and visceral involvement to severe neurological disease. Neuronopathic patients display dramatic neuronal loss and increased neuroinflammation, whose molecular basis are still unclear. Using a combination of Drosophila dGBA1b loss-of-function models and GD patient-derived iPSCs differentiated towards neuronal precursors and mature neurons we showed that different GD- tissues and neuronal cells display an impairment of growth mechanisms with an increased cell death and reduced proliferation. These phenotypes are coupled with the downregulation of several Hippo transcriptional targets, mainly involved in cells and tissue growth, and YAP exclusion from nuclei. Interestingly, Hippo knock-down in the GBA-KO flies rescues the proliferative defect, suggesting that targeting the Hippo pathway can be a promising therapeutic approach to neuronopathic GD.
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- 2023
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3. P405: IN VITRO RESPONSE TO BCL-2 INHIBITION IN PEDIATRIC B PRECURSOR ALL WITH HIGH RISK CYTOGENETICS
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Francesca Gottardi, Daria Messelodi, Domenico D’amico, Francesco Baccelli, Davide Leardini, Salvatore Nicola Bertuccio, and Riccardo Masetti
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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4. Immune dysregulation associated with co-occurring germline CBL and SH2B3 variants
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Francesco Baccelli, Davide Leardini, Edoardo Muratore, Daria Messelodi, Salvatore Nicola Bertuccio, Maria Chiriaco, Caterina Cancrini, Francesca Conti, Fausto Castagnetti, Lucia Pedace, Andrea Pession, Ayami Yoshimi, Charlotte Niemeyer, Marco Tartaglia, Franco Locatelli, and Riccardo Masetti
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CBL ,JMML ,Immune dysregulation ,CBL syndrome ,SH2B3 ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background CBL syndrome is a RASopathy caused by heterozygous germline mutations of the Casitas B-lineage lymphoma (CBL) gene. It is characterized by heterogeneous clinical phenotype, including developmental delay, facial dysmorphisms, cardiovascular malformations and an increased risk of cancer development, particularly juvenile myelomonocytic leukemia (JMML). Although the clinical phenotype has been progressively defined in recent years, immunological manifestations have not been well elucidated to date. Methods We studied the genetic, immunological, coagulative, and clinical profile of a family with CBL syndrome that came to our observation after the diagnosis of JMML, with homozygous CBL mutation, in one of the members. Results Variant analysis revealed the co-occurrence of CBL heterozygous mutation (c.1141 T > C) and SH2B3 mutation (c.1697G > A) in two other members. Patients carrying both mutations showed an ALPS-like phenotype characterized by lymphoproliferation, cytopenia, increased double-negative T-cells, impaired Fas-mediated lymphocyte apoptosis, altered cell death in PBMC and low TRECs expression. A coagulative work-up was also performed and showed the presence of subclinical coagulative alterations in patients carrying both mutations. Conclusion In the reported family, we described immune dysregulation, as part of the clinical spectrum of CBL mutation with the co-occurrence of SH2B3.
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- 2022
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5. Peripheral blood cellular profile at pre-lymphodepletion is associated with CD19-targeted CAR-T cell-associated neurotoxicity
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Serena De Matteis, Michele Dicataldo, Beatrice Casadei, Gianluca Storci, Noemi Laprovitera, Mario Arpinati, Enrico Maffini, Pietro Cortelli, Maria Guarino, Francesca Vaglio, Maria Naddeo, Barbara Sinigaglia, Luca Zazzeroni, Serafina Guadagnuolo, Enrica Tomassini, Salvatore Nicola Bertuccio, Daria Messelodi, Manuela Ferracin, Massimiliano Bonafè, Pier Luigi Zinzani, and Francesca Bonifazi
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chimeric antigen receptor ,senescence ,inflammation ,neurotoxicity ,myeloid activation ,Immunologic diseases. Allergy ,RC581-607 - Abstract
BackgroundInfusion of second generation autologous CD19-targeted chimeric antigen receptor (CAR) T cells in patients with R/R relapsed/refractory B-cell lymphoma (BCL) is affected by inflammatory complications, such as Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). Current literature suggests that the immune profile prior to CAR-T infusion modifies the chance to develop ICANS.MethodsThis is a monocenter prospective study on 53 patients receiving approved CAR T-cell products (29 axi-cel, 24 tisa-cel) for R/R-BCL. Clinical, biochemical, and hematological variables were analyzed at the time of pre-lymphodepletion (pre-LD). In a subset of 21 patients whose fresh peripheral blood sample was available, we performed cytofluorimetric analysis of leukocytes and extracellular vesicles (EVs). Moreover, we assessed a panel of soluble plasma biomarkers (IL-6/IL-10/GDF-15/IL-15/CXCL9/NfL) and microRNAs (miR-146a-5p, miR-21-5p, miR-126-3p, miR-150-5p) which are associated with senescence and inflammation.ResultsMultivariate analysis at the pre-LD time-point in the entire cohort (n=53) showed that a lower percentage of CD3+CD8+ lymphocytes (38.6% vs 46.8%, OR=0.937 [95% CI: 0.882-0.996], p=0.035) and higher levels of serum C-reactive protein (CRP, 4.52 mg/dl vs 1.00 mg/dl, OR=7.133 [95% CI: 1.796-28], p=0.005) are associated with ICANS. In the pre-LD samples of 21 patients, a significant increase in the percentage of CD8+CD45RA+CD57+ senescent cells (median % value: 16.50% vs 9.10%, p=0.009) and monocytic-myeloid derived suppressor cells (M-MDSC, median % value: 4.4 vs 1.8, p=0.020) was found in ICANS patients. These latter also showed increased levels of EVs carrying CD14+ and CD45+ myeloid markers, of the myeloid chemokine CXCL-9, as well of the MDSC-secreted cytokine IL-10. Notably, the serum levels of circulating neurofilament light chain, a marker of neuroaxonal injury, were positively correlated with the levels of senescent CD8+ T cells, M-MDSC, IL-10 and CXCL-9. No variation in the levels of the selected miRNAs was observed between ICANS and no-ICANS patients.DiscussionOur data support the notion that pre-CAR-T systemic inflammation is associated with ICANS. Higher proportion of senescence CD8+ T cells and M-MDSC correlate with early signs of neuroaxonal injury at pre-LD time-point, suggesting that ICANS may be the final event of a process that begins before CAR-T infusion, consequence to patient clinical history.
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- 2023
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6. Case report: Senescence as mechanism of resistance to Pembrolizumab in a Lymphoma patient who failed CD19-Targeted CAR-T cell therapy
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Serena De Matteis, Beatrice Casadei, Ginevra Lolli, Michele Dicataldo, Francesco Barbato, Elisa Dan, Andrea Paccagnella, Barbara Sinigaglia, Clara Bertuzzi, Annalisa Arcari, Luca Zazzeroni, Patrizia Bernuzzi, Noemi Laprovitera, Gianluca Storci, Salvatore Nicola Bertuccio, Manuela Ferracin, Massimiliano Bonafè, Pier Luigi Zinzani, and Francesca Bonifazi
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lymphoma ,senescence ,exhaustion ,chimeric antigen receptor (CAR T) ,pembrolizumab ,resistance ,Immunologic diseases. Allergy ,RC581-607 - Abstract
BackgroundT cells engineered to target CD19 antigen on neoplastic B cells represent the most striking example of CAR-T cell therapy. The success rate of this therapy is affected by several limitations: target antigen loss, and/or acquisition of a senescent/exhausted phenotype by CAR and non-CAR T cells.Case presentationWe report on a patient affected by refractory Diffuse Large B-cell Lymphoma who was resistant to CAR T-cell therapy and to two cycles post CAR-T of pembrolizumab (PBZ) due to the evolution into a B-cell Hodgkin-like lymphoma. Owing to the CD30 expression and the Hodgkin-like phenotype, the patient was ultimately treated with Brentuximab-Vedotin and finally underwent remission. Upon PBZ treatment, 100% of circulating CAR-T+ cells showed a persistent CD8+ senescent/exhausted phenotype, while an increase in the percentage of senescent cells was found in the non-CAR CD8+ T cells compartment.ConclusionsPBZ is not able to reinvigorate exhausted CAR+ T cells and to confer durable clinical response. We hypothesize that the phenomenon is due to the senescent phenotype of CAR+ T cells, which did not allow PBZ-induced reactivation and proliferative rescue. The phenomenon, together with the loss of CAR-T target CD19 and the shift of non-CAR CD8+ T cells towards a senescent phenotype likely contributed to set up an immune landscape with poor antitumor capacity.
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- 2022
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7. Molecular Signature of Biological Aggressiveness in Clear Cell Sarcoma of the Kidney (CCSK)
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Michele Fiore, Alberto Taddia, Valentina Indio, Salvatore Nicola Bertuccio, Daria Messelodi, Salvatore Serravalle, Jessica Bandini, Filippo Spreafico, Daniela Perotti, Paola Collini, Andrea Di Cataldo, Gianandrea Pasquinelli, Francesca Chiarini, Maura Fois, Fraia Melchionda, Andrea Pession, and Annalisa Astolfi
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CCSK ,FGF3 ,BCOR ,internal tandem duplication ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Clear cell sarcoma of the kidney (CCSK) is a rare pediatric renal tumor with a worse prognosis than Wilms’ tumor. Although recently, BCOR internal tandem duplication (ITD) has been found as a driver mutation in more than 80% of cases, a deep molecular characterization of this tumor is still lacking, as well as its correlation with the clinical course. The aim of this study was to investigate the differential molecular signature between metastatic and localized BCOR-ITD-positive CCSK at diagnosis. Whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) were performed on six localized and three metastatic BCOR-ITD-positive CCSKs, confirming that this tumor carries a low mutational burden. No significant recurrences of somatic or germline mutations other than BCOR-ITD were identified among the evaluated samples. Supervised analysis of gene expression data showed enrichment of hundreds of genes, with a significant overrepresentation of the MAPK signaling pathway in metastatic cases (p < 0.0001). Within the molecular signature of metastatic CCSK, five genes were highly and significantly over-expressed: FGF3, VEGFA, SPP1, ADM, and JUND. The role of FGF3 in the acquisition of a more aggressive phenotype was investigated in a cell model system obtained by introducing the ITD into the last exon of BCOR by Crispr/Cas9 gene editing of the HEK-293 cell line. Treatment with FGF3 of BCOR-ITD HEK-293 cell line induced a significant increase in cell migration versus both untreated and scramble cell clone. The identification of over-expressed genes in metastatic CCSKs, with a particular focus on FGF3, could offer new prognostic and therapeutic targets in more aggressive cases.
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- 2023
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8. The Pediatric Acute Leukemia Fusion Oncogene ETO2-GLIS2 Increases Self-Renewal and Alters Differentiation in a Human Induced Pluripotent Stem Cells-Derived Model
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Salvatore Nicola Bertuccio, Fabien Boudia, Marie Cambot, Cécile K. Lopez, Larissa Lordier, Alessandro Donada, Elie Robert, Cécile Thirant, Zakia Aid, Salvatore Serravalle, Annalisa Astolfi, Valentina Indio, Franco Locatelli, Andrea Pession, William Vainchenker, Riccardo Masetti, Hana Raslova, and Thomas Mercher
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2020
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9. Are Induced Pluripotent Stem Cells a Step towards Modeling Pediatric Leukemias?
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Salvatore Nicola Bertuccio, Davide Leardini, Daria Messelodi, Laura Anselmi, Francesca Manente, Federico Ragni, Salvatore Serravalle, Riccardo Masetti, and Andrea Pession
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pediatric leukemia ,in vitro modeling ,iPSCs ,genome editing ,new target therapies ,Cytology ,QH573-671 - Abstract
Despite enormous improvements in pre-clinical and clinical research, acute leukemia still represents an open challenge for pediatric hematologists; both for a significant relapse rate and for long term therapy-related sequelae. In this context, the use of an innovative technology, such as induced pluripotent stem cells (iPSCs), allows to finely reproduce the primary features of the malignancy and can be exploited as a model to study the onset and development of leukemia in vitro. The aim of this review is to explore the recent literature describing iPSCs as a key tool to study different types of hematological malignancies, comprising acute myeloid leukemia, non-down syndrome acute megakaryoblastic leukemia, B cell acute lymphoblastic leukemia, and juvenile myelomonocytic leukemia. This model demonstrates a positive impact on pediatric hematological diseases, especially in those affecting infants whose onsets is found in fetal hematopoiesis. This evidence highlights the importance of achieving an in vitro representation of the human embryonic hematopoietic development and timing-specific modifications, either genetic or epigenetic. Moreover, further insights into clonal evolution studies shed light in the way of a new precision medicine era, where patient-oriented decisions and therapies could further improve the outcome of pediatric cases. Nonetheless, we will also discuss here the difficulties and limitations of this model.
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- 2022
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10. iPSC-Derived Gaucher Macrophages Display Growth Impairment and Activation of Inflammation-Related Cell Death
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Daria Messelodi, Salvatore Nicola Bertuccio, Valentina Indio, Silvia Strocchi, Alberto Taddia, Salvatore Serravalle, Jessica Bandini, Annalisa Astolfi, and Andrea Pession
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Gaucher disease ,iPSC ,macrophages ,inflammation ,necroptosis ,Cytology ,QH573-671 - Abstract
Gaucher disease is a lysosomal storage disorder characterized by β-glucosidase enzyme deficiency and substrate accumulation, especially in cells of the reticuloendothelial system. Typical features of the disease are the unrestrained activation of inflammatory mechanisms, whose molecular pathways are still unclear. To investigate biological mechanisms underlying the macrophage activation in GD, we derived iPSCs from a healthy donor and a GD patient line and differentiated them into hematopoietic progenitors. While GD iPSCs are able to efficiently give rise to CD33+/CD45+ myeloid progenitors, the maturation towards the CD14+/CD163+ monocyte/macrophages fate resulted enhanced in the GD lines, that in addition displayed a decreased growth potential compared to control cells either in semisolid or in liquid culture. The GD lines growth impairment was associated with a significant upregulation of RIPK3 and MLKL, two key effectors of necroptosis, the inflammation related cell death pathway. The activation of necroptosis, which has already been linked to neuronopathic GD, may play a role in the disease proinflammatory condition and in the identified cell growth defects. Understanding the GD macrophage role in the alteration of mechanisms linked to cellular metabolism imbalance, cell death and inflammation are crucial in identifying new ways to approach the disease.
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- 2021
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11. Necrotizing Enterocolitis: Overview on In Vitro Models
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Luigia De Fazio, Isadora Beghetti, Salvatore Nicola Bertuccio, Concetta Marsico, Silvia Martini, Riccardo Masetti, Andrea Pession, Luigi Corvaglia, and Arianna Aceti
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necrotizing enterocolitis ,preterm infants ,in vitro models ,cellular lines ,intestinal organoids ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Necrotizing enterocolitis (NEC) is a gut inflammatory disorder which constitutes one of the leading causes of morbidity and mortality for preterm infants. The pathophysiology of NEC is yet to be fully understood; several observational studies have led to the identification of multiple factors involved in the pathophysiology of the disease, including gut immaturity and dysbiosis of the intestinal microbiome. Given the complex interactions between microbiota, enterocytes, and immune cells, and the limited access to fetal human tissues for experimental studies, animal models have long been essential to describe NEC mechanisms. However, at present there is no animal model perfectly mimicking human NEC; furthermore, the disease mechanisms appear too complex to be studied in single-cell cultures. Thus, researchers have developed new approaches in which intestinal epithelial cells are exposed to a combination of environmental and microbial factors which can potentially trigger NEC. In addition, organoids have gained increasing attention as promising models for studying NEC development. Currently, several in vitro models have been proposed and have contributed to describe the disease in deeper detail. In this paper, we will provide an updated review of available in vitro models of NEC and an overview of current knowledge regarding its molecular underpinnings.
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- 2021
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12. Hh/Gli antagonist in acute myeloid leukemia with CBFA2T3-GLIS2 fusion gene
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Riccardo Masetti, Salvatore Nicola Bertuccio, Annalisa Astolfi, Francesca Chiarini, Annalisa Lonetti, Valentina Indio, Matilde De Luca, Jessica Bandini, Salvatore Serravalle, Monica Franzoni, Martina Pigazzi, Alberto Maria Martelli, Giuseppe Basso, Franco Locatelli, and Andrea Pession
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Acute myeloid leukemia ,Acute megakaryoblastic leukemia ,CBFA2T3-GLIS2 ,GANT61 ,Hedgehog pathway ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background CBFA2T3-GLIS2 is a fusion gene found in 17% of non-Down syndrome acute megakaryoblastic leukemia (non-DS AMKL, FAB M7) and in 8% of pediatric cytogenetically normal acute myeloid leukemia (CN-AML, in association with several French-American-British (FAB) subtypes). Children with AML harboring this aberration have a poor outcome, regardless of the FAB subtype. This fusion gene drives a peculiar expression pattern and leads to overexpression of some of Hedgehog-related genes. GLI-similar protein 2 (GLIS2) is closely related to the GLI family, the final effectors of classic Hedgehog pathway. These observations lend compelling support to the application of GLI inhibitors in the treatment of AML with the aberration CBFA2T3-GLIS2. GANT61 is, nowadays, the most potent inhibitor of GLI family proteins. Methods We exposed to GANT61 AML cell lines and primary cells positive and negative for CBFA2T3-GLIS2 and analyzed the effect on cellular viability, induction of apoptosis, cell cycle, and expression profile. Results As compared to AML cells without GLIS2 fusion, GANT61 exposure resulted in higher sensitivity of both cell lines and primary AML cells carrying CBFA2T3-GLIS2 to undergo apoptosis and G1 cell cycle arrest. Remarkably, gene expression studies demonstrated downregulation of GLIS2-specific signature genes in both treated cell lines and primary cells, in comparison with untreated cells. Moreover, chromatin immunoprecipitation analysis revealed direct regulation by GLIS2 chimeric protein of DNMT1 and DNMT3B, two genes implicated in important epigenetic functions. Conclusions Our findings indicate that the GLI inhibitor GANT61 may be used to specifically target the CBFA2T3-GLIS2 fusion gene in pediatric AML.
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- 2017
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13. Insights on the Interplay between Cells Metabolism and Signaling: A Therapeutic Perspective in Pediatric Acute Leukemias
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Laura Anselmi, Salvatore Nicola Bertuccio, Annalisa Lonetti, Arcangelo Prete, Riccardo Masetti, and Andrea Pession
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metabolism/metabolomics ,leukemia ,pediatric tumors ,molecular approaches ,signal transduction inhibitors ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Nowadays, thanks to extensive studies and progress in precision medicine, pediatric leukemia has reached an extremely high overall survival rate. Nonetheless, a fraction of relapses and refractory cases is still present, which are frequently correlated with poor prognosis. Although several molecular features of these diseases are known, still the field of energy metabolism, which is widely studied in adult, has not been frequently explored in childhood leukemias. Metabolic reprogramming is a hallmark of cancer and is deeply connected with other genetic and signaling aberrations generally known to be key features of both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). This review aims to clear the current knowledge on metabolic rewiring in pediatric ALL and AML, also highlighting the influence of the main signaling pathways and suggesting potential ideas to further exploit this field to discover new prognostic biomarkers and, above all, beneficial therapeutic options.
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- 2020
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14. ERCC6L2-related disease: a novel entity of bone marrow failure disorder with high risk of clonal evolution
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Francesco Baccelli, Davide Leardini, Sara Cerasi, Daria Messelodi, Salvatore Nicola Bertuccio, and Riccardo Masetti
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Hematology ,General Medicine - Abstract
ERCC excision repair 6 like 2 (ERCC6L2) gene encodes for different helicase-like protein members of the Snf2 family involved in transcription-coupled nucleotide excision repair and in cell proliferation. Germline homozygous mutations in children and adults predispose to a peculiar bone marrow failure phenotype characterized by mild hematological alterations with a high risk of developing acute myeloid leukemia. The outcome for patients with leukemia progression is dismal while patients undergoing hematopoietic stem cell transplantation in the early stage have better outcomes. The ERCC6L2-related hematological disease presents a high penetrance, posing important questions regarding the treatment strategies and possible preemptive approaches. This review describes the biological function of ERCC6L2 and the clinical manifestations of the associated disease, trying to focus on the unsolved clinical questions.
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- 2023
15. Torque teno mini virus as a cause of childhood acute promyelocytic leukemia lacking PML/RARA fusion
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Matteo Carella, Stefano Volinia, Riccardo Masetti, Salvatore Nicola Bertuccio, Virginia Libri, Andrea Pession, Valentina Indio, Simone Rampelli, Annalisa Astolfi, Davide Leardini, Marco Candela, Daria Messelodi, Jessica Bandini, Salvatore Serravalle, Astolfi A., Masetti R., Indio V., Bertuccio S.N., Messelodi D., Rampelli S., Leardini D., Carella M., Serravalle S., Libri V., Bandini J., Volinia S., Candela M., and Pession A.
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Torque teno mini virus ,Oncogene Proteins, Fusion ,business.industry ,Karyotype ,Immunology ,Tretinoin ,Cell Biology ,Hematology ,Biochemistry ,Virology ,Antineoplastic Agent ,Leukemia, Promyelocytic, Acute ,Medicine ,Female ,Child ,business ,Human ,Childhood Acute Promyelocytic Leukemia - Abstract
Astolf et al provide the first report of acute promyelocytic leukemia driven by viral insertion into the RARA locus. This represents a clear demonstration of a pathology driven by the member of the anelloviruses, a group of viruses otherwise thought to have minimal or no pathogenic potential.
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- 2021
16. Mesenchymal Stromal Cell Secretome in Acute Myeloid Leukemia Bone Marrow Niche
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Giulia Borella, Giorgia Longo, Ambra Da Ros, Elisabetta Campodoni, Margherita Montanari, Maddalena Benetton, Salvatore Nicola Bertuccio, Monica Sandri, Claudia Tregnago, Riccardo Masetti, Franco Locatelli, and Martina Pigazzi
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
17. Uncommon cytogenetic abnormalities identifying high-risk acute myeloid leukemia in children
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Vanessa Guidi, Andrea Pession, Salvatore Nicola Bertuccio, Riccardo Masetti, Sara Cerasi, Annalisa Lonetti, Masetti R., Bertuccio S.N., Guidi V., Cerasi S., Lonetti A., and Pession A.
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Poor prognosis ,risk stratification ,Aggressive disease ,Pediatric AML ,poor prognosi ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Molecular Targeted Therapy ,Target therapy ,Child ,Genetic Association Studies ,pediatric AML ,Chromosome Aberrations ,cytogenetic lesion ,target therapy ,business.industry ,Pediatric acute myeloid leukemia ,Age Factors ,Disease Management ,Myeloid leukemia ,General Medicine ,Prognosis ,diagnosi ,Leukemia, Myeloid, Acute ,030104 developmental biology ,030220 oncology & carcinogenesis ,Risk stratification ,business - Abstract
Pediatric acute myeloid leukemia (AML) represents an aggressive disease and is the leading cause of childhood leukemic mortality. The genomic landscape of pediatric AML has been recently mapped and redefined thanks to large-scale sequencing efforts. Today, understanding how to incorporate the growing list of genetic lesions into a risk stratification algorithm for pediatric AML is increasingly challenging given the uncertainty regarding the prognostic impact of rare lesions. Here we review some uncommon cytogenetic lesions to be considered for inclusion in the high-risk groups of the next pediatric AML treatment protocols. We describe their main clinical characteristics, biological background and outcome. We also provide some suggestions for the management of these rare but challenging patients and some novel targeted therapeutic options.
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- 2020
18. iPSC-Derived Gaucher Macrophages Display Growth Impairment and Activation of Inflammation-Related Cell Death
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Annalisa Astolfi, Andrea Pession, Jessica Bandini, Salvatore Nicola Bertuccio, Alberto Taddia, Salvatore Serravalle, Valentina Indio, Silvia Strocchi, Daria Messelodi, Messelodi D., Bertuccio S.N., Indio V., Strocchi S., Taddia A., Serravalle S., Bandini J., Astolfi A., and Pession A.
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Necroptosi ,Programmed cell death ,Macrophage ,QH301-705.5 ,Protein Kinase ,Necroptosis ,Induced Pluripotent Stem Cells ,necroptosis ,Monocyte ,Induced Pluripotent Stem Cell ,Article ,Monocytes ,Proinflammatory cytokine ,medicine ,Humans ,Cell Lineage ,Biology (General) ,Progenitor cell ,Cell Proliferation ,Inflammation ,iPSC ,Gaucher Disease ,Cell Death ,Chemistry ,Cell growth ,Macrophages ,Cell Differentiation ,General Medicine ,Macrophage Activation ,Cell biology ,medicine.anatomical_structure ,Receptor-Interacting Protein Serine-Threonine Kinases ,CD163 ,Protein Kinases ,Human - Abstract
Gaucher disease is a lysosomal storage disorder characterized by β-glucosidase enzyme deficiency and substrate accumulation, especially in cells of the reticuloendothelial system. Typical features of the disease are the unrestrained activation of inflammatory mechanisms, whose molecular pathways are still unclear. To investigate biological mechanisms underlying the macrophage activation in GD, we derived iPSCs from a healthy donor and a GD patient line and differentiated them into hematopoietic progenitors. While GD iPSCs are able to efficiently give rise to CD33+/CD45+ myeloid progenitors, the maturation towards the CD14+/CD163+ monocyte/macrophages fate resulted enhanced in the GD lines, that in addition displayed a decreased growth potential compared to control cells either in semisolid or in liquid culture. The GD lines growth impairment was associated with a significant upregulation of RIPK3 and MLKL, two key effectors of necroptosis, the inflammation related cell death pathway. The activation of necroptosis, which has already been linked to neuronopathic GD, may play a role in the disease proinflammatory condition and in the identified cell growth defects. Understanding the GD macrophage role in the alteration of mechanisms linked to cellular metabolism imbalance, cell death and inflammation are crucial in identifying new ways to approach the disease.
- Published
- 2021
19. AML-283 The Genetic Landscape of NUP98-Rearranged Pediatric Leukemia
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Masayuki Umeda, Nicole Michmerhuizen, Jing Ma, Tamara Westover, Michael P Walsh, Guangchun Song, Cristina Mecucci, Danika Di Giacomo, Franco Locatelli, Riccardo Masetti, Salvatore Nicola Bertuccio, Martina Pigazzi, Ilaria Iacobucci, Charles G Mullighan, and Jeffery M Klco
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Cancer Research ,Oncology ,Hematology - Published
- 2022
20. Poster: AML-283 The Genetic Landscape of NUP98-Rearranged Pediatric Leukemia
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Masayuki Umeda, Nicole Michmerhuizen, Jing Ma, Tamara Westover, Michael P Walsh, Guangchun Song, Cristina Mecucci, Danika Di Giacomo, Franco Locatelli, Riccardo Masetti, Salvatore Nicola Bertuccio, Martina Pigazzi, Ilaria Iacobucci, Charles G Mullighan, and Jeffery M Klco
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Cancer Research ,Oncology ,Hematology - Published
- 2022
21. Hippo and necroptosis pathways are involved in cell growth defects in Gaucher disease
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Davide Leardini, Alberto Taddia, Daniela Grifoni, Salvatore Nicola Bertuccio, Silvia Strocchi, Andrea Pession, Annalisa Astolfi, Annalisa Pession, Daria Messelodi, and Annalisa Astolfi, Daria Messelodi, Silvia Strocchi, Salvatore Nicola Bertuccio, Alberto Taddia, Annalisa Pession, Daniela Grifoni, Andrea Pession
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Gaucher Disease ,iPSC ,biology ,Endocrinology, Diabetes and Metabolism ,Necroptosis ,Disease ,biology.organism_classification ,Biochemistry ,Cell biology ,NO ,Endocrinology ,Gaucher Disease, iPSC, Drosophila ,Genetics ,Drosophila ,Drosophila (subgenus) ,Molecular Biology - Abstract
Gaucher disease (GD) is a monogenic disorder characterized byβ-glucocerebrosidase enzyme deficiency. Typical features of the diseaseare the unrestrained activation of inflammatory mechanisms andneuronal cell death in neuronopathic conditions, whose molecularpathways are still not fully understood. Recent evidences show thatupregulation of the Hippo pathway is associated with neuroinflamma-tion and neuronal cell death. We analyzed the Hippo pathway activitytaking advantage of a Drosophila Gaucher-like model characterized bydGBA1b knock-out (GBA1bKO).WefoundderegulationofCycE,dIAPandMYC, direct targets of the pathway both in Drosophila and mammals,which were severely reduced at transcript and protein level,suggestingacell growth impairment. Analyzing upstream components we foundthat Fat, an atypical cadherin upstream of the kinase complex, wasupregulated. Moreover the glypicans Dally and Dally-like, known to benegatively regulated by Fat and involved in glial and synapsedevelopment, were found downregulated in the GBA1bKObackground,supporting a role in neurological damage. On the other hand, theaberrant inflammatory condition of the hematological compartmentwas investigated in the human model of induced Pluripotent Stem Cells(iPSC), differentiated into hematopoietic progenitors. While GD iPSCswere able to differentiate into CD34+/CD43+/CD45+ progenitors, theyshowed a decreased proliferative potential compared to healthy donoriPSC either in semisolid and liquid culture, therefore exhibiting a growthimpairment. This effect was coupled with the activation of necroptosispathway with a significant upregulation of RIPK3 and MLKL both in thepluripotent and differentiated state. Correction of the mutation to rescuethe phenotype is ongoing, taking advantage of AAVS1 editing approachin order to develop a fully comparable cell model useful in a cell therapyperspective. These data obtained with suitable GD models support therole of Hippo and necroptosis effectors in GD, amenable of furtherconsideration as potential therapeutic targets.
- Published
- 2019
22. Inhibition of methyltransferase dot1l sensitizes to sorafenib treatment aml cells irrespective of mll-rearrangements: A novel therapeutic strategy for pediatric aml
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Andrea Pession, Annalisa Astolfi, Francesca Chiarini, Annalisa Lonetti, Valentina Indio, Riccardo Masetti, Salvatore Nicola Bertuccio, Maria Antonella Laginestra, Giuseppe Tarantino, Franco Locatelli, Alberto M. Martelli, Lonetti A., Indio V., Laginestra M.A., Tarantino G., Chiarini F., Astolfi A., Bertuccio S.N., Martelli A.M., Locatelli F., Pession A., and Masetti R.
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0301 basic medicine ,Sorafenib ,Cancer Research ,Methyltransferase ,Cellular differentiation ,medicine.medical_treatment ,lcsh:RC254-282 ,Article ,Targeted therapy ,NO ,BRAF ,Pediatric acute myeloid leukemia ,03 medical and health sciences ,0302 clinical medicine ,Pinometostat ,hemic and lymphatic diseases ,medicine ,ChIP-seq ,DOT1L ,neoplasms ,business.industry ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Leukemia ,030104 developmental biology ,Oncology ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Cell culture ,Apoptosis ,030220 oncology & carcinogenesis ,Cancer research ,business ,medicine.drug - Abstract
Pediatric acute myeloid leukemia (AML) is an aggressive malignancy with poor prognosis for which there are few effective targeted approaches, despite the numerous genetic alterations, including MLL gene rearrangements (MLL-r). The histone methyltransferase DOT1L is involved in supporting the proliferation of MLL-r cells, for which a target inhibitor, Pinometostat, has been evaluated in a clinical trial recruiting pediatric MLL-r leukemic patients. However, modest clinical effects have been observed. Recent studies have reported that additional leukemia subtypes lacking MLL-r are sensitive to DOT1L inhibition. Here, we report that targeting DOT1L with Pinometostat sensitizes pediatric AML cells to further treatment with the multi-kinase inhibitor Sorafenib, irrespectively of MLL-r. DOT1L pharmacologic inhibition induces AML cell differentiation and modulates the expression of genes with relevant roles in cancer development. Such modifications in the transcriptional program increase the apoptosis and growth suppression of both AML cell lines and primary pediatric AML cells with diverse genotypes. Through ChIP-seq analysis, we identified the genes regulated by DOT1L irrespective of MLL-r, including the Sorafenib target BRAF, providing mechanistic insights into the drug combination activity. Our results highlight a novel therapeutic strategy for pediatric AML patients.
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- 2020
23. Insights on the Interplay between Cells Metabolism and Signaling: A Therapeutic Perspective in Pediatric Acute Leukemias
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Arcangelo Prete, Andrea Pession, Salvatore Nicola Bertuccio, Riccardo Masetti, Annalisa Lonetti, Laura Anselmi, Anselmi Laura, Bertuccio S.N., Lonetti A., Prete A., Masetti R., and Pession A.
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Poor prognosis ,metabolism/metabolomic ,molecular approaches ,Metabolic reprogramming ,Antineoplastic Agents ,Review ,Bioinformatics ,signal transduction inhibitors ,Catalysis ,lcsh:Chemistry ,Inorganic Chemistry ,Recurrence ,hemic and lymphatic diseases ,medicine ,molecular approache ,Humans ,Gene Regulatory Networks ,Precision Medicine ,Physical and Theoretical Chemistry ,Child ,lcsh:QH301-705.5 ,Molecular Biology ,Spectroscopy ,pediatric tumor ,Pediatric leukemia ,Clinical Trials as Topic ,business.industry ,Organic Chemistry ,leukemia ,Myeloid leukemia ,Cancer ,General Medicine ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,medicine.disease ,Precision medicine ,pediatric tumors ,Computer Science Applications ,Leukemia, Myeloid, Acute ,Leukemia ,lcsh:Biology (General) ,lcsh:QD1-999 ,Signal transduction ,Energy Metabolism ,metabolism/metabolomics ,business ,Signal Transduction - Abstract
Nowadays, thanks to extensive studies and progress in precision medicine, pediatric leukemia has reached an extremely high overall survival rate. Nonetheless, a fraction of relapses and refractory cases is still present, which are frequently correlated with poor prognosis. Although several molecular features of these diseases are known, still the field of energy metabolism, which is widely studied in adult, has not been frequently explored in childhood leukemias. Metabolic reprogramming is a hallmark of cancer and is deeply connected with other genetic and signaling aberrations generally known to be key features of both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). This review aims to clear the current knowledge on metabolic rewiring in pediatric ALL and AML, also highlighting the influence of the main signaling pathways and suggesting potential ideas to further exploit this field to discover new prognostic biomarkers and, above all, beneficial therapeutic options.
- Published
- 2020
24. The pediatric acute leukemia fusion oncogene ETO2-GLIS2 increases self-renewal and alters differentiation in a human induced pluripotent stem cells-derived model
- Author
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Franco Locatelli, Salvatore Serravalle, Cécile Thirant, Andrea Pession, Riccardo Masetti, Annalisa Astolfi, William Vainchenker, Valentina Indio, Alessandro Donada, Zakia Aid, Thomas Mercher, Salvatore Nicola Bertuccio, Elie Robert, Hana Raslova, Fabien Boudia, Larissa Lordier, Cécile K. Lopez, Marie Cambot, Bertuccio, SN, Boudia, F, Cambot, M, Lopez, CK, Lordier, L, Donada, A, Robert, E, Thirant, C, Aid, Z, Serravalle, S, Astolfi, A, Indio, V, Locatelli, F, Pession, A, Vainchenker, W, Masetti, R, Raslova, H, and Mercher, T
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Letter ,Biology ,Self renewal ,NO ,03 medical and health sciences ,0302 clinical medicine ,Text mining ,GLIS2 ,Human Induced Pluripotent Stem Cells ,030304 developmental biology ,0303 health sciences ,Acute leukemia ,Oncogene ,lcsh:RC633-647.5 ,business.industry ,lcsh:Diseases of the blood and blood-forming organs ,Hematology ,3. Good health ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,030220 oncology & carcinogenesis ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,ETO2-GLIS2 ,Cancer research ,na ,business - Abstract
Supplemental Digital Content is available in the text.
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- 2020
25. Messa a punto di modelli cellulari umani per lo studio della malattia di Gaucher
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Daria Messelodi, Silvia Strocchi, Salvatore Nicola Bertuccio, Daniela Grifoni, Annalisa Pession, Annalisa Astolfi, Andrea Pession, and Daria Messelodi, Silvia Strocchi, Salvatore Nicola Bertuccio,Daniela Grifoni, Annalisa Pession, Annalisa Astolfi, Andrea Pession
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iPSC ,disease modeling ,Gaucher disease ,Gaucher disease, iPSC, disease modeling ,NO - Abstract
La malattia di Gaucher è un disordine monogenico caratterizzato dal deficit dell’enzima β-glucocerebrosidasi. Dal momento che l’innesco aberrante di meccanismi infiammatori cellulari è un aspetto peculiare della malattia, ci siamo concentrati sullo studio del pathway della necroptosi, forma di morte cellulare programmata dettata dall’infiammazione. Dall’analisi dell’espressione genica e dalla valutazione dei livelli proteici in modelli cellulari Gaucher-like, ottenuti tramite inibizione enzimatica, abbiamo evidenziato come la chinasi RIP1, primo effettore della via di segnalazione sia iperattivato nello stato patologico. Per disporre di un sistema d’analisi più accurato stiamo mettendo a punto modelli che sfruttano cellule staminali pluripotenti indotte (iPSCs) derivate da paziente e donatore sano. Tramite gene editing la più comune mutazione puntiforme causante la malattia (N370S), è stata inserita in iPSCs derivate da donatore sano. Le cellule sono state trasfettate, tramite nucleofezione, con il plasmide pSpCas9(BB)-2A-Puro codificante per la Cas9 e per una guida a RNA in grado di indirizzarne il taglio sito-specifico. La sequenza stampo per l’inserimento della mutazione è stata introdotta sotto forma di DNA a singolo filamento. La presenza della mutazione è stata verificata tramite PCR effettuata con primer specifici su pool di cellule trasfettate. Parallelamente, da cellule mononucleate del sangue periferico di un paziente Gaucher con mutazione N370S/L444P sono state ottenute iPSCs grazie a trasduzione con i vettori virali Sendai codificanti per i fattori di riprogrammazione: Klf4, cMyc e KOS. Il monitoraggio del differenziamento verso destino ematopoietico sarà portato avanti concentrandosi nello specifico sul tipo cellulare macrofagico in quanto maggior target dell’accumulo sfingolipidico caratterizzante la malattia.
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- 2018
26. Necrotizing Enterocolitis: Overview on In Vitro Models
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Riccardo Masetti, Isadora Beghetti, Andrea Pession, Silvia Martini, Luigi Corvaglia, Luigia De Fazio, Arianna Aceti, Salvatore Nicola Bertuccio, Concetta Marsico, De Fazio, Luigia, Beghetti, Isadora, Bertuccio, Salvatore Nicola, Marsico, Concetta, Martini, Silvia, Masetti, Riccardo, Pession, Andrea, Corvaglia, Luigi, and Aceti, Arianna
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0301 basic medicine ,QH301-705.5 ,necrotizing enterocoliti ,Review ,Disease ,Bioinformatics ,Catalysis ,Inorganic Chemistry ,Limited access ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Enterocolitis, Necrotizing ,medicine ,Animals ,Humans ,preterm infants ,Biology (General) ,Physical and Theoretical Chemistry ,QD1-999 ,Molecular Biology ,Spectroscopy ,in vitro models ,necrotizing enterocolitis ,business.industry ,Organic Chemistry ,intestinal organoid ,General Medicine ,medicine.disease ,cellular lines ,digestive system diseases ,In vitro ,Gastrointestinal Microbiome ,Computer Science Applications ,Disease Models, Animal ,Chemistry ,030104 developmental biology ,intestinal organoids ,in vitro model ,030220 oncology & carcinogenesis ,cellular line ,Intestinal Microbiome ,Necrotizing enterocolitis ,Dysbiosis ,business ,Inflammatory disorder - Abstract
Necrotizing enterocolitis (NEC) is a gut inflammatory disorder which constitutes one of the leading causes of morbidity and mortality for preterm infants. The pathophysiology of NEC is yet to be fully understood; several observational studies have led to the identification of multiple factors involved in the pathophysiology of the disease, including gut immaturity and dysbiosis of the intestinal microbiome. Given the complex interactions between microbiota, enterocytes, and immune cells, and the limited access to fetal human tissues for experimental studies, animal models have long been essential to describe NEC mechanisms. However, at present there is no animal model perfectly mimicking human NEC; furthermore, the disease mechanisms appear too complex to be studied in single-cell cultures. Thus, researchers have developed new approaches in which intestinal epithelial cells are exposed to a combination of environmental and microbial factors which can potentially trigger NEC. In addition, organoids have gained increasing attention as promising models for studying NEC development. Currently, several in vitro models have been proposed and have contributed to describe the disease in deeper detail. In this paper, we will provide an updated review of available in vitro models of NEC and an overview of current knowledge regarding its molecular underpinnings.
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- 2021
27. BCOR involvement in cancer
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Andrea Pession, Annalisa Astolfi, Fraia Melchionda, Salvatore Nicola Bertuccio, Michele Fiore, Valentina Indio, Astolfi, Annalisa, Fiore, Michele, Melchionda, Fraia, Indio, Valentina, Bertuccio, Salvatore N, and Pession, Andrea
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0301 basic medicine ,Cancer Research ,Clear-cell sarcoma of the kidney ,Cellular differentiation ,Review ,Cyclin B ,Biology ,medicine.disease_cause ,NO ,Central Nervous System Neoplasms ,03 medical and health sciences ,0302 clinical medicine ,oncogenesis ,Neoplasms ,Proto-Oncogene Proteins ,Genetics ,medicine ,Humans ,ESS ,Epigenetics ,BCOR ,Polycomb Repressive Complex 1 ,PRC1.1 ,Endometrial stromal sarcoma ,epigenetics ,CCSK ,CNS-HGNET-BCOR ,ITD ,PRC2 ,SRBCS ,RNA-Binding Proteins ,Cancer ,Sarcoma ,medicine.disease ,Repressor Proteins ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,Trans-Activators ,Cancer research ,biology.protein ,Carcinogenesis ,epigenetic - Abstract
BCOR is a gene that encodes for an epigenetic regulator involved in the specification of cell differentiation and body structure development and takes part in the noncanonical polycomb repressive complex 1. This review provides a comprehensive summary of BCOR’s involvement in oncology, illustrating that various BCOR aberrations, such as the internal tandem duplications of the PCGF Ub-like fold discriminator domain and different gene fusions (mainly BCOR–CCNB3, BCOR–MAML3 and ZC3H7B–BCOR), represent driver elements of various sarcomas such as clear cell sarcoma of the kidney, primitive mesenchymal myxoid tumor of infancy, small round blue cell sarcoma, endometrial stromal sarcoma and histologically heterogeneous CNS neoplasms group with similar genomic methylation patterns known as CNS-HGNET-BCOR. Furthermore, other BCOR alterations (often loss of function mutations) recur in a large variety of mesenchymal, epithelial, neural and hematological tumors, suggesting a central role in cancer evolution.
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- 2019
28. Targeting Hedgehog pathway in pediatric acute myeloid leukemia: challenges and opportunities
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Salvatore Nicola Bertuccio, Franco Locatelli, Annalisa Lonetti, Andrea Pession, Riccardo Masetti, Pession, Andrea, Lonetti, Annalisa, Bertuccio, Salvatore, Locatelli, Franco, and Masetti, Riccardo
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0301 basic medicine ,Myeloid ,Clinical Biochemistry ,Antineoplastic Agents ,Biology ,Hedgehog pathway ,03 medical and health sciences ,0302 clinical medicine ,Drug Discovery ,medicine ,Animals ,Humans ,Hedgehog Proteins ,Child ,Hedgehog ,Pharmacology ,target therapy ,Drug Discovery3003 Pharmaceutical Science ,Pediatric acute myeloid leukemia ,pediatric acute myeloid leukemia ,refractory acute myeloid leukemia ,medicine.disease ,Molecular medicine ,Embryonic stem cell ,Hedgehog signaling pathway ,Signaling system ,Leukemia, Myeloid, Acute ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine - Abstract
The Hedgehog (Hh) pathway is a key signaling system that controls proliferation and differentiation of embryonic cells, whereas in adult organisms it is involved in the control of tissue homeostasi...
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- 2019
29. CBFA2T3-GLIS2-positive acute myeloid leukaemia. A peculiar paediatric entity
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Andrea Pession, Riccardo Masetti, Franco Locatelli, Salvatore Nicola Bertuccio, Masetti, Riccardo, Bertuccio, Salvatore N., Pession, Andrea, and Locatelli, Franco
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Male ,medicine.medical_specialty ,Adolescent ,Oncogene Proteins, Fusion ,acute megakaryoblastic leukaemia ,acute myeloid leukaemia ,CBFA2T3-GLIS2 ,childhood leukaemia ,leukaemia diagnosis ,Kruppel-Like Transcription Factors ,Reviews ,Review ,Biology ,Bioinformatics ,Disease-Free Survival ,Fusion gene ,CBFA2T3‐GLIS2 ,03 medical and health sciences ,0302 clinical medicine ,Chromosome 16 ,GLIS2 ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Overall survival ,Animals ,Humans ,Acute megakaryoblastic leukaemia ,Child ,Hematology ,Oncogene ,Tumor Suppressor Proteins ,Infant, Newborn ,Infant ,Repressor Proteins ,Survival Rate ,Leukemia, Myeloid, Acute ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Child, Preschool ,030220 oncology & carcinogenesis ,leukaemia diagnosi ,Female ,Myeloid leukaemia ,Chromosomes, Human, Pair 16 ,030215 immunology - Abstract
Summary The scenario of paediatric acute myeloid leukaemia (AML), particularly non‐Down syndrome acute megakaryoblastic leukaemia (non‐DS‐AMKL), has been recently revolutionized by the advent of large‐scale, genomic sequencing technologies. In this changing landscape, a significantly relevant discovery has been represented by the identification of the CBFA2T3‐GLIS2 fusion gene, which is the result of a cryptic inversion of chromosome 16. It is the most frequent chimeric oncogene identified to date in non‐DS‐AMKL, although it seems not to be exclusively restricted to the French‐American‐British M7 subgroup. The CBFA2T3‐GLIS2 fusion gene characterizes a subtype of leukaemia that is specific to paediatrics, having never been identified in adults. It characterizes an extremely aggressive leukaemia, as the presence of this fusion is associated with a grim outcome in almost all of the case series reported, with overall survival rates ranging between 15% and 30%. Although the molecular basis that underlies this leukaemia subtype is still far from being completely elucidated, unique functional properties induced by CBFA2T3‐GLIS2 in the leukaemogenesis driving process have been recently identified. We here review the peculiarities of CBFA2T3‐GLIS2‐positive AML, describing its intriguing clinical and biological behaviour and providing some challenging targeting opportunities.
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- 2019
30. Exploiting Clonal Evolution to Improve the Diagnosis and Treatment Efficacy Prediction in Pediatric AML
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Andrea Pession, Laura Anselmi, Riccardo Masetti, Sara Cerasi, Salvatore Nicola Bertuccio, Sara Polidori, Salvatore Serravalle, Annalisa Lonetti, Bertuccio S.N., Anselmi L., Masetti R., Lonetti A., Cerasi S., Polidori S., Serravalle S., and Pession A.
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,clonal evolution ,Context (language use) ,Review ,Disease ,Somatic evolution in cancer ,Pediatric AML ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,RC254-282 ,pediatric AML ,target therapy ,business.industry ,Genetic heterogeneity ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Myeloid leukemia ,Treatment efficacy ,030104 developmental biology ,NGS ,030220 oncology & carcinogenesis ,business - Abstract
Simple Summary The use of innovative technologies has revolutionized cancer research in recent years, and in the field of pediatric oncohematology, great results have been achieved. However, within this context, acute myeloid leukemia still represents a considerable challenge for clinicians, as frequent cases of relapse or refractory disease, especially in specific subgroups, remain present. With this review, the authors aim to recapitulate the main features of this extremely heterogeneous malignancy, by highlighting the concept of clonal evolution and how, thanks also to the impact of new high throughput techniques, this could be exploited to deepen the current knowledge on molecular mechanisms driving this disease. Overall, this study will seek to pave the way for making new tools available to further improve diagnosis and treatment protocols in pediatric patients. Abstract Despite improvements in therapeutic protocols and in risk stratification, acute myeloid leukemia (AML) remains the leading cause of childhood leukemic mortality. Indeed, the overall survival accounts for ~70% but still ~30% of pediatric patients experience relapse, with poor response to conventional chemotherapy. Thus, there is an urgent need to improve diagnosis and treatment efficacy prediction in the context of this disease. Nowadays, in the era of high throughput techniques, AML has emerged as an extremely heterogeneous disease from a genetic point of view. Different subclones characterized by specific molecular profiles display different degrees of susceptibility to conventional treatments. In this review, we describe in detail this genetic heterogeneity of pediatric AML and how it is linked to relapse in terms of clonal evolution. We highlight some innovative tools to characterize minor subclones that could help to enhance diagnosis and a preclinical model suitable for drugs screening. The final ambition of research is represented by targeted therapy, which could improve the prognosis of pediatric AML patients, as well as to limit the side toxicity of current treatments.
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- 2021
31. Hh/Gli antagonist in acute myeloid leukemia with CBFA2T3-GLIS2 fusion gene
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Salvatore Serravalle, Andrea Pession, Matilde De Luca, Annalisa Astolfi, Francesca Chiarini, Salvatore Nicola Bertuccio, Franco Locatelli, Martina Pigazzi, Annalisa Lonetti, Jessica Bandini, Riccardo Masetti, Giuseppe Basso, Alberto M. Martelli, Monica Franzoni, Valentina Indio, Riccardo Masetti, Salvatore Nicola Bertuccio, Annalisa Astolfi, Francesca Chiarini, Annalisa Lonetti, Valentina Indio, Matilde De Luca, Jessica Bandini, Salvatore Serravalle, Monica Franzoni, Martina Pigazzi, Alberto Maria Martelli, Giuseppe Basso, Franco Locatelli, and Andrea Pession
- Subjects
Myeloid ,0301 basic medicine ,Cancer Research ,Oncogene Proteins, Fusion ,Pyridines ,Apoptosis ,Hedgehog pathway ,Fusion gene ,Acute megakaryoblastic leukemia ,0302 clinical medicine ,Gene expression ,Tumor Cells, Cultured ,Acute myeloid leukemia ,CBFA2T3-GLIS2 ,GANT61 ,Cell Cycle Checkpoints ,Child ,Down-Regulation ,Hedgehog Proteins ,Humans ,Kruppel-Like Transcription Factors ,Leukemia, Myeloid, Acute ,Pyrimidines ,Repressor Proteins ,Tumor Suppressor Proteins ,Zinc Finger Protein GLI1 ,Hematology ,Molecular Biology ,Oncology ,Letter to the Editor ,Oncogene Proteins ,Leukemia ,Cultured ,CBFA2T3/GLIS2 Fusion Gene ,Myeloid leukemia ,lcsh:Diseases of the blood and blood-forming organs ,Cell cycle ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Tumor Cells ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,030220 oncology & carcinogenesis ,Acute ,Biology ,lcsh:RC254-282 ,NO ,03 medical and health sciences ,medicine ,Fusion ,lcsh:RC633-647.5 ,medicine.disease ,Fusion protein ,030104 developmental biology ,Cancer research ,DNMT1 - Abstract
Background CBFA2T3-GLIS2 is a fusion gene found in 17% of non-Down syndrome acute megakaryoblastic leukemia (non-DS AMKL, FAB M7) and in 8% of pediatric cytogenetically normal acute myeloid leukemia (CN-AML, in association with several French-American-British (FAB) subtypes). Children with AML harboring this aberration have a poor outcome, regardless of the FAB subtype. This fusion gene drives a peculiar expression pattern and leads to overexpression of some of Hedgehog-related genes. GLI-similar protein 2 (GLIS2) is closely related to the GLI family, the final effectors of classic Hedgehog pathway. These observations lend compelling support to the application of GLI inhibitors in the treatment of AML with the aberration CBFA2T3-GLIS2. GANT61 is, nowadays, the most potent inhibitor of GLI family proteins. Methods We exposed to GANT61 AML cell lines and primary cells positive and negative for CBFA2T3-GLIS2 and analyzed the effect on cellular viability, induction of apoptosis, cell cycle, and expression profile. Results As compared to AML cells without GLIS2 fusion, GANT61 exposure resulted in higher sensitivity of both cell lines and primary AML cells carrying CBFA2T3-GLIS2 to undergo apoptosis and G1 cell cycle arrest. Remarkably, gene expression studies demonstrated downregulation of GLIS2-specific signature genes in both treated cell lines and primary cells, in comparison with untreated cells. Moreover, chromatin immunoprecipitation analysis revealed direct regulation by GLIS2 chimeric protein of DNMT1 and DNMT3B, two genes implicated in important epigenetic functions. Conclusions Our findings indicate that the GLI inhibitor GANT61 may be used to specifically target the CBFA2T3-GLIS2 fusion gene in pediatric AML. Electronic supplementary material The online version of this article (doi:10.1186/s13045-017-0396-0) contains supplementary material, which is available to authorized users.
- Published
- 2017
32. Identification of a cytogenetic and molecular subgroup of acute myeloid leukemias showing sensitivity to L-Asparaginase
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Annalisa Astolfi, Fraia Melchionda, Andrea Pession, Salvatore Serravalle, Annalisa Lonetti, Anna Leszl, Valentina Indio, Salvatore Nicola Bertuccio, Bertuccio, SALVATORE NICOLA, Serravalle, S, Astolfi, Annalisa, Lonetti, Annalisa, Indio, Valentina, Leszl, A, Pession, Andrea, and Melchionda, Fraia
- Subjects
0301 basic medicine ,Programmed cell death ,Monosomy ,Myeloid ,acute myeloid leukemia ,NO ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,hemic and lymphatic diseases ,medicine ,L-Asparaginase ,neoplasms ,Chromosome 7 (human) ,Gene knockdown ,business.industry ,ASNS gene ,medicine.disease ,monosomy chromosome 7 ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Cell culture ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,business ,Haploinsufficiency ,Research Paper - Abstract
L-Asparaginase (L-Asp) is an enzyme that catalyzes the hydrolysis of L-asparagine to L-aspartic acid, and its depletion induces leukemic cell death. L-Asp is an important component of treatment regimens for Acute Lymphoblastic Leukemia (ALL). Sensitivity to L-Asp is due to the absence of L-Asparagine synthetase (ASNS), the enzyme that catalyzes the biosynthesis of L-asparagine. ASNS gene is located on 7q21.3, and its increased expression in ALLs correlates with L-Asp resistance. Chromosome 7 monosomy (-7) is a recurrent aberration in myeloid disorders, particularly in adverse-risk Acute Myeloid Leukemias (AMLs) and therapy-related myeloid neoplasms (t-MN), that leads to a significant downregulation of the deleted genes, including ASNS. Therefore, we hypothesized that -7 could affect L-Asp sensitivity in AMLs. By treating AML cell lines and primary cells from pediatric patients with L-Asp, we showed that -7 cells were more sensitive than AML cells without -7. Importantly, both ASNS gene and protein expression were significantly lower in -7 AML cell lines, suggesting that haploinsufficiency of ASNS might induce sensitivity to L-Asp in AMLs. To prove the role of ASNS haploinsufficiency in sensitizing AML cells to L-Asp treatment, we performed siRNA-knockdown of ASNS in AML cell lines lacking -7, and observed that ASNS knockdown significantly increased L-Asp cytotoxicity. In conclusion, -7 AMLs showed high sensitivity to L-Asp treatment due to low expression of ASNS. Thus, L-Asp may be considered for treatment of AML pediatric patients carrying -7, in order to improve the outcome of adverse-risk AMLs and t-MN patients.
- Published
- 2017
33. Genomic complexity and dynamics of clonal evolution in childhood acute myeloid leukemia studied with whole-exome sequencing
- Author
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Martina Pigazzi, Giuseppe Tarantino, Annalisa Astolfi, Tamara Belotti, Andrea Pession, Salvatore Serravalle, Giuseppe Basso, Valentina Indio, Marco Togni, Franco Locatelli, Salvatore Nicola Bertuccio, Marco Zecca, Riccardo Masetti, Ilaria Castelli, Masetti, Riccardo, Castelli, Ilaria, Astolfi, Annalisa, Bertuccio, SALVATORE NICOLA, Indio, Valentina, Togni, Marco, Belotti, Tamara, Serravalle, Salvatore, Tarantino, Giuseppe, Zecca, Marco, Pigazzi, Martina, Basso, Giuseppe, Pession, Andrea, and Locatelli, Franco
- Subjects
0301 basic medicine ,Oncology ,Male ,medicine.medical_specialty ,Adolescent ,Pediatric Hematology/Oncology ,DNA Mutational Analysis ,acute myeloid leukemia relapse ,Somatic evolution in cancer ,NO ,Clonal Evolution ,03 medical and health sciences ,Acute myeloid leukemia relapse ,FLT3-TKD mutation ,Pediatric acute myeloid leukemia ,SETD2 mutation ,Whole-exome massively parallel sequencing ,Internal medicine ,medicine ,Humans ,Exome ,Child ,Exome sequencing ,Massive parallel sequencing ,business.industry ,Childhood Acute Myeloid Leukemia ,Remission Induction ,pediatric acute myeloid leukemia ,Myeloid leukemia ,High-Throughput Nucleotide Sequencing ,Genomics ,medicine.disease ,PTPN11 ,flt3-tkd mutation ,setd2 mutation ,whole-exome massively parallel sequencing ,Leukemia ,Leukemia, Myeloid, Acute ,030104 developmental biology ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Child, Preschool ,Immunology ,Female ,Neoplasm Recurrence, Local ,business ,Research Paper - Abstract
// Riccardo Masetti 1, * , Ilaria Castelli 1, * , Annalisa Astolfi 2 , Salvatore Nicola Bertuccio 1 , Valentina Indio 2 , Marco Togni 1, 3 , Tamara Belotti 1 , Salvatore Serravalle 1 , Giuseppe Tarantino 2 , Marco Zecca 4 , Martina Pigazzi 5 , Giuseppe Basso 5 , Andrea Pession 1, # , Franco Locatelli 6, 7, # 1 Department of Pediatrics “Lalla Seragnoli”, Hematology-Oncology Unit, University of Bologna, Bologna, Italy 2 Interdepartmental Centre of Cancer Research “G. Prodi”, University of Bologna, Bologna, Italy 3 Current address: Stem Cell Group, University College London Cancer Institute, University College London, London, United Kingdom 4 Department of Pediatric Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy 5 Department of Woman and Child Health, Laboratory of Hematology-Oncology, University of Padova, Padova, Italy 6 Department of Pediatric Hematology-Oncology, IRCCS Ospedale Bambino Gesu, Rome, Italy 7 University of Pavia, Pavia, Italy * These authors have contributed equally to this work # Both authors have shared co-senior authorship Correspondence to: Riccardo Masetti, email: riccardo.masetti@gmail.com Keywords: pediatric acute myeloid leukemia, acute myeloid leukemia relapse, whole-exome massively parallel sequencing, SETD2 mutation, FLT3-TKD mutation Received: April 19, 2016 Accepted: July 10, 2016 Published: July 22, 2016 ABSTRACT Despite significant improvement in treatment of childhood acute myeloid leukemia (AML), 30% of patients experience disease recurrence, which is still the major cause of treatment failure and death in these patients. To investigate molecular mechanisms underlying relapse, we performed whole-exome sequencing of diagnosis-relapse pairs and matched remission samples from 4 pediatric AML patients without recurrent cytogenetic alterations. Candidate driver mutations were selected for targeted deep sequencing at high coverage, suitable to detect small subclones (0.12%). BiCEBPα mutation was found to be stable and highly penetrant, representing a separate biological and clinical entity, unlike WT1 mutations, which were extremely unstable. Among the mutational patterns underlying relapse, we detected the acquisition of proliferative advantage by signaling activation (PTPN11 and FLT3-TKD mutations) and the increased resistance to apoptosis (hyperactivation of TYK2). We also found a previously undescribed feature of AML, consisting of a hypermutator phenotype caused by SETD2 inactivation. The consequent accumulation of new mutations promotes the adaptability of the leukemia, contributing to clonal selection. We report a novel ASXL3 mutation characterizing a very small subclone (
- Published
- 2016
34. Synergistic cytotoxic effect of l-asparaginase combined with decitabine as a demethylating agent in pediatric T-ALL, with specific epigenetic signature
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Annalisa Astolfi, Salvatore Nicola Bertuccio, Fraia Melchionda, Andrea Pession, Salvatore Serravalle, Serravalle, Salvatore, Bertuccio, SALVATORE NICOLA, Astolfi, Annalisa, Melchionda, Fraia, and Pession, Andrea
- Subjects
Genetics and Molecular Biology (all) ,0301 basic medicine ,Immunology and Microbiology (all) ,lcsh:Medicine ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,Biochemistry ,Epigenesis, Genetic ,chemistry.chemical_compound ,Gene expression ,Cytotoxic T cell ,Tumor ,Aspartate-Ammonia Ligase ,Drug Synergism ,General Medicine ,Methylation ,Combination ,DNA methylation ,Azacitidine ,Drug Therapy, Combination ,Drug ,Asparagine ,Research Article ,medicine.drug ,Human ,Article Subject ,Cell Survival ,Decitabine ,Biology ,General Biochemistry, Genetics and Molecular Biology ,NO ,Cell Line ,Dose-Response Relationship ,03 medical and health sciences ,Drug Therapy ,Genetic ,Cell Line, Tumor ,medicine ,Humans ,Epigenetics ,Gene ,Biochemistry, Genetics and Molecular Biology (all) ,General Immunology and Microbiology ,Dose-Response Relationship, Drug ,lcsh:R ,DNA Methylation ,Molecular biology ,Epigenesis ,Transcriptome ,Demethylating agent ,030104 developmental biology ,chemistry ,Cancer research - Abstract
T-Acute Lymphoblastic Leukemia (T-ALL) remains a subgroup of pediatric ALL, with a lower response to standard chemotherapy. Some recent studies established the fundamental role of epigenetic aberrations such as DNA hypermethylation, to influence patients’ outcome and response to chemotherapy. Moreover, L-asparaginase is an important chemotherapeutic agent for treatment of ALL and resistance to this drug has been linked toASNSexpression, which can be silenced through methylation. Therefore, we tested whether the sensitivity of T-ALL cell lines towards L-asparaginase is correlated to the epigenetic status ofASNSgene and whether the sensitivity can be modified by concurrent demethylating treatment. Hence we treated different T-ALL cell lines with L-asparaginase and correlated different responses to the treatment withASNSexpression. Then we demonstrated that theASNSexpression was dependent on the methylation status of the promoter. Finally we showed that, despite the demethylating effect on theASNSgene expression, the combined treatment with the demethylating agent Decitabine could synergistically improve the L-asparaginase sensitivity in those T-ALL cell lines characterized by hypermethylation of theASNSgene. In conclusion, this preclinical study identified an unexpected synergistic activity of L-asparaginase and Decitabine in the subgroup of T-ALL with lowASNSexpression due to hypermethylation of theASNSpromoter, while it did not restore sensitivity in the resistant cell lines characterized by higherASNSexpression.
- Published
- 2016
35. [Typhoid fever and acute pancreatitis: two cases]
- Author
-
Ferdinando, Rombolà and Salvatore Nicola, Bertuccio
- Subjects
Adult ,Male ,Serine Proteinase Inhibitors ,Gabexate ,Ceftriaxone ,Anti-Ulcer Agents ,Octreotide ,Abdominal Pain ,Anti-Bacterial Agents ,Pancreatitis ,Acute Disease ,Humans ,Female ,Typhoid Fever ,Omeprazole - Abstract
Acute pancreatitis is a pancreatic inflammation that recognises Salmonella typhi among its aetiological agents. In this article the authors describe two cases of acute pancreatitis secondary to typhoid fever, evolving towards complete recovery. These two cases, besides confirming that Salmonella typhi can be responsible for acute pancreatitis, remind us that during typhoid fever, amylase enzyme test should be always assessed. Moreover, salmonella infection must also be considered in cases of non-alcoholic or non-lithiasic pancreatitis.
- Published
- 2007
36. HCV infection and pericarditis: an extrahepatic manifestation?
- Author
-
Salvatore Nicola, Bertuccio, Ferdinando, Rombolà, Antonia, Bertuccio, and Francesco Salvatore, Ranieri
- Subjects
Adult ,Time Factors ,Aspirin ,Hepacivirus ,Hepatitis C Antibodies ,Hepatitis C, Chronic ,Length of Stay ,Polymerase Chain Reaction ,Hospitalization ,Electrocardiography ,Acute Disease ,Humans ,Pericarditis ,RNA, Viral ,Platelet Aggregation Inhibitors ,Follow-Up Studies - Abstract
The authors describe a clinical case in which they found the unusual combination of acute hepatitis caused by HCV and pericarditis in a young person, resulting in complete recovery from the pericarditis but in a deterioration of the chronic HCV. A close examination of the literature on this subject revealed that, although no similar case was recorded, an aetiological relationship between the hepatitis C virus and pericarditis cannot be excluded since an HCV infection often gives rise to extra-hepatic cardiac problems.
- Published
- 2005
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