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  1. Artikel ; Online: The Cyclin-dependent kinase 1: more than a cell cycle regulator.

    Massacci, Giorgia / Perfetto, Livia / Sacco, Francesca

    British journal of cancer

    2023  Band 129, Heft 11, Seite(n) 1707–1716

    Abstract: The Cyclin-dependent kinase 1, as a serine/threonine protein kinase, is more than a cell cycle regulator as it was originally identified. During the last decade, it has been shown to carry out versatile functions during the last decade. From cell cycle ... ...

    Abstract The Cyclin-dependent kinase 1, as a serine/threonine protein kinase, is more than a cell cycle regulator as it was originally identified. During the last decade, it has been shown to carry out versatile functions during the last decade. From cell cycle control to gene expression regulation and apoptosis, CDK1 is intimately involved in many cellular events that are vital for cell survival. Here, we provide a comprehensive catalogue of the CDK1 upstream regulators and substrates, describing how this kinase is implicated in the control of key 'cell cycle-unrelated' biological processes. Finally, we describe how deregulation of CDK1 expression and activation has been closely associated with cancer progression and drug resistance.
    Mesh-Begriff(e) Humans ; CDC2 Protein Kinase/genetics ; CDC2 Protein Kinase/metabolism ; Protein Serine-Threonine Kinases/genetics ; Genes, cdc ; Cell Cycle ; Cell Division
    Chemische Substanzen CDC2 Protein Kinase (EC 2.7.11.22) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
    Sprache Englisch
    Erscheinungsdatum 2023-10-28
    Erscheinungsland England
    Dokumenttyp Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 80075-2
    ISSN 1532-1827 ; 0007-0920
    ISSN (online) 1532-1827
    ISSN 0007-0920
    DOI 10.1038/s41416-023-02468-8
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Phosphoproteomics and Organelle Proteomics in Pancreatic Islets.

    Caliskan, Özüm Sehnaz / Massacci, Giorgia / Krahmer, Natalie / Sacco, Francesca

    Methods in molecular biology (Clifton, N.J.)

    2022  Band 2456, Seite(n) 123–140

    Abstract: Over the recent years, mass spectrometry (MS)-based proteomics has undergone dramatic advances in sample preparation, instrumentation, and computational methods. Here, we describe in detail, how a workflow quantifies global protein phosphorylation in ... ...

    Abstract Over the recent years, mass spectrometry (MS)-based proteomics has undergone dramatic advances in sample preparation, instrumentation, and computational methods. Here, we describe in detail, how a workflow quantifies global protein phosphorylation in pancreatic islets and characterizes intracellular organelle composition on protein level by MS-based proteomics.
    Mesh-Begriff(e) Islets of Langerhans/metabolism ; Mass Spectrometry/methods ; Organelles/metabolism ; Phosphorylation ; Proteomics/methods
    Sprache Englisch
    Erscheinungsdatum 2022-05-25
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-2124-0_9
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel: Combining Mass Spectrometry-Based Phosphoproteomics with a Network-Based Approach to Reveal FLT3-Dependent Mechanisms of Chemoresistance.

    Pugliese, Giusj Monia / Latini, Sara / Massacci, Giorgia / Perfetto, Livia / Sacco, Francesca

    Proteomes

    2021  Band 9, Heft 2

    Abstract: FLT3 mutations are the most frequently identified genetic alterations in acute myeloid leukemia (AML) and are associated with poor clinical outcome, relapse and chemotherapeutic resistance. Elucidating the molecular mechanisms underlying FLT3-dependent ... ...

    Abstract FLT3 mutations are the most frequently identified genetic alterations in acute myeloid leukemia (AML) and are associated with poor clinical outcome, relapse and chemotherapeutic resistance. Elucidating the molecular mechanisms underlying FLT3-dependent pathogenesis and drug resistance is a crucial goal of biomedical research. Given the complexity and intricacy of protein signaling networks, deciphering the molecular basis of FLT3-driven drug resistance requires a systems approach. Here we discuss how the recent advances in mass spectrometry (MS)-based (phospho) proteomics and multiparametric analysis accompanied by emerging computational approaches offer a platform to obtain and systematically analyze cell-specific signaling networks and to identify new potential therapeutic targets.
    Sprache Englisch
    Erscheinungsdatum 2021-04-27
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article ; Review
    ZDB-ID 2720995-7
    ISSN 2227-7382
    ISSN 2227-7382
    DOI 10.3390/proteomes9020019
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel: Transcription Factor Activation Profiles (TFAP) identify compounds promoting differentiation of Acute Myeloid Leukemia cell lines.

    Riccio, Federica / Micarelli, Elisa / Secci, Riccardo / Giuliani, Giulio / Vumbaca, Simone / Massacci, Giorgia / Castagnoli, Luisa / Fuoco, Claudia / Cesareni, Gianni

    Cell death discovery

    2022  Band 8, Heft 1, Seite(n) 16

    Abstract: Repurposing of drugs for new therapeutic use has received considerable attention for its potential to limit time and cost of drug development. Here we present a new strategy to identify chemicals that are likely to promote a desired phenotype. We used ... ...

    Abstract Repurposing of drugs for new therapeutic use has received considerable attention for its potential to limit time and cost of drug development. Here we present a new strategy to identify chemicals that are likely to promote a desired phenotype. We used data from the Connectivity Map (CMap) to produce a ranked list of drugs according to their potential to activate transcription factors that mediate myeloid differentiation of leukemic progenitor cells. To validate our strategy, we tested the in vitro differentiation potential of candidate compounds using the HL-60 human cell line as a myeloid differentiation model. Ten out of 22 compounds, which were ranked high in the inferred list, were confirmed to promote significant differentiation of HL-60. These compounds may be considered candidate for differentiation therapy. The method that we have developed is versatile and it can be adapted to different drug repurposing projects.
    Sprache Englisch
    Erscheinungsdatum 2022-01-10
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ISSN 2058-7716
    ISSN 2058-7716
    DOI 10.1038/s41420-021-00811-7
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel ; Online: Unveiling the signaling network of FLT3-ITD AML improves drug sensitivity prediction.

    Latini, Sara / Venafra, Veronica / Massacci, Giorgia / Bica, Valeria / Graziosi, Simone / Pugliese, Giusj Monia / Iannuccelli, Marta / Frioni, Filippo / Minnella, Gessica / Marra, John Donald / Chiusolo, Patrizia / Pepe, Gerardo / Helmer Citterich, Manuela / Mougiakakos, Dimitros / Böttcher, Martin / Fischer, Thomas / Perfetto, Livia / Sacco, Francesca

    eLife

    2024  Band 12

    Abstract: Currently, the identification of patient-specific therapies in cancer is mainly informed by personalized genomic analysis. In the setting of acute myeloid leukemia (AML), patient-drug treatment matching fails in a subset of patients harboring atypical ... ...

    Abstract Currently, the identification of patient-specific therapies in cancer is mainly informed by personalized genomic analysis. In the setting of acute myeloid leukemia (AML), patient-drug treatment matching fails in a subset of patients harboring atypical internal tandem duplications (ITDs) in the tyrosine kinase domain of the FLT3 gene. To address this unmet medical need, here we develop a systems-based strategy that integrates multiparametric analysis of crucial signaling pathways, and patient-specific genomic and transcriptomic data with a prior knowledge signaling network using a Boolean-based formalism. By this approach, we derive personalized predictive models describing the signaling landscape of AML FLT3-ITD positive cell lines and patients. These models enable us to derive mechanistic insight into drug resistance mechanisms and suggest novel opportunities for combinatorial treatments. Interestingly, our analysis reveals that the JNK kinase pathway plays a crucial role in the tyrosine kinase inhibitor response of FLT3-ITD cells through cell cycle regulation. Finally, our work shows that patient-specific logic models have the potential to inform precision medicine approaches.
    Mesh-Begriff(e) Humans ; Signal Transduction ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; MAP Kinase Signaling System ; Cell Line ; Drug Resistance ; fms-Like Tyrosine Kinase 3/genetics
    Chemische Substanzen FLT3 protein, human (EC 2.7.10.1) ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1)
    Sprache Englisch
    Erscheinungsdatum 2024-04-02
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.90532
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel ; Online: Impact of FLT3-ITD location on cytarabine sensitivity in AML: a network-based approach.

    Pugliese, Giusj Monia / Venafra, Veronica / Bica, Valeria / Massacci, Giorgia / Latini, Sara / Graziosi, Simone / Fischer, Thomas / Mougiakakos, Dimitrios / Boettcher, Martin / Perfetto, Livia / Sacco, Francesca

    Leukemia

    2023  Band 37, Heft 5, Seite(n) 1151–1155

    Mesh-Begriff(e) Humans ; Cytarabine/pharmacology ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Cell Line, Tumor ; fms-Like Tyrosine Kinase 3/genetics ; Mutation
    Chemische Substanzen Cytarabine (04079A1RDZ) ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1) ; FLT3 protein, human (EC 2.7.10.1)
    Sprache Englisch
    Erscheinungsdatum 2023-03-25
    Erscheinungsland England
    Dokumenttyp Research Support, Non-U.S. Gov't ; Letter
    ZDB-ID 807030-1
    ISSN 1476-5551 ; 0887-6924
    ISSN (online) 1476-5551
    ISSN 0887-6924
    DOI 10.1038/s41375-023-01881-5
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  7. Artikel: Integrating Patient-Specific Information into Logic Models of Complex Diseases: Application to Acute Myeloid Leukemia.

    Palma, Alessandro / Iannuccelli, Marta / Rozzo, Ilaria / Licata, Luana / Perfetto, Livia / Massacci, Giorgia / Castagnoli, Luisa / Cesareni, Gianni / Sacco, Francesca

    Journal of personalized medicine

    2021  Band 11, Heft 2

    Abstract: High throughput technologies such as deep sequencing and proteomics are increasingly becoming mainstream in clinical practice and support diagnosis and patient stratification. Developing computational models that recapitulate cell physiology and its ... ...

    Abstract High throughput technologies such as deep sequencing and proteomics are increasingly becoming mainstream in clinical practice and support diagnosis and patient stratification. Developing computational models that recapitulate cell physiology and its perturbations in disease is a required step to help with the interpretation of results of high content experiments and to devise personalized treatments. As complete cell-models are difficult to achieve, given limited experimental information and insurmountable computational problems, approximate approaches should be considered. We present here a general approach to modeling complex diseases by embedding patient-specific genomics data into actionable logic models that take into account prior knowledge. We apply the strategy to acute myeloid leukemia (AML) and assemble a network of logical relationships linking most of the genes that are found frequently mutated in AML patients. We derive Boolean models from this network and we show that by priming the model with genomic data we can infer relevant patient-specific clinical features. Here we propose that the integration of literature-derived causal networks with patient-specific data should be explored to help bedside decisions.
    Sprache Englisch
    Erscheinungsdatum 2021-02-10
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article
    ZDB-ID 2662248-8
    ISSN 2075-4426
    ISSN 2075-4426
    DOI 10.3390/jpm11020117
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  8. Artikel ; Online: A key role of the WEE1-CDK1 axis in mediating TKI-therapy resistance in FLT3-ITD positive acute myeloid leukemia patients.

    Massacci, Giorgia / Venafra, Veronica / Latini, Sara / Bica, Valeria / Pugliese, Giusj Monia / Graziosi, Simone / Klingelhuber, Felix / Krahmer, Natalie / Fischer, Thomas / Mougiakakos, Dimitrios / Boettcher, Martin / Perfetto, Livia / Sacco, Francesca

    Leukemia

    2022  Band 37, Heft 2, Seite(n) 288–297

    Abstract: The insertion site of the internal tandem duplications (ITDs) in the FLT3 gene affects the sensitivity to tyrosine kinase inhibitors (TKIs) therapy in acute myeloid leukemia (AML). Patients with the ITD in the tyrosine kinase domain lack effective ... ...

    Abstract The insertion site of the internal tandem duplications (ITDs) in the FLT3 gene affects the sensitivity to tyrosine kinase inhibitors (TKIs) therapy in acute myeloid leukemia (AML). Patients with the ITD in the tyrosine kinase domain lack effective therapeutic options. Here, to identify genotype-driven strategies increasing the TKI therapy efficacy, we developed SignalingProfiler, a strategy supporting the integration of high-sensitive mass spectrometry-based (phospho)proteomics, RNA sequencing datasets with literature-derived signaling networks. The approach generated FLT3-ITD genotype-specific predictive models and revealed a conserved role of the WEE1-CDK1 axis in TKIs resistance. Remarkably, pharmacological inhibition of the WEE1 kinase synergizes and strengthens the pro-apoptotic effect of TKIs therapy in cell lines and patient-derived primary blasts. Finally, we propose a new molecular mechanism of TKIs resistance in AML and suggest the combination of WEE1 inhibitor and TKI as a therapeutic option to improve patients clinical outcome.
    Mesh-Begriff(e) Humans ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Drug Resistance, Neoplasm/genetics ; Cell Line ; Signal Transduction ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; fms-Like Tyrosine Kinase 3/genetics ; fms-Like Tyrosine Kinase 3/metabolism ; Mutation ; Protein-Tyrosine Kinases/genetics ; Protein-Tyrosine Kinases/metabolism ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; CDC2 Protein Kinase/genetics ; CDC2 Protein Kinase/metabolism ; CDC2 Protein Kinase/pharmacology
    Chemische Substanzen Protein Kinase Inhibitors ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1) ; FLT3 protein, human (EC 2.7.10.1) ; WEE1 protein, human (EC 2.7.10.2) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Cell Cycle Proteins ; CDK1 protein, human (EC 2.7.11.22) ; CDC2 Protein Kinase (EC 2.7.11.22)
    Sprache Englisch
    Erscheinungsdatum 2022-12-12
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 807030-1
    ISSN 1476-5551 ; 0887-6924
    ISSN (online) 1476-5551
    ISSN 0887-6924
    DOI 10.1038/s41375-022-01785-w
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  9. Artikel: A Resource for the Network Representation of Cell Perturbations Caused by SARS-CoV-2 Infection

    Perfetto, Livia / Micarelli, Elisa / Iannuccelli, Marta / Lo Surdo, Prisca / Giuliani, Giulio / Latini, Sara / Pugliese, Giusj Monia / Massacci, Giorgia / Vumbaca, Simone / Riccio, Federica / Fuoco, Claudia / Paoluzi, Serena / Castagnoli, Luisa / Cesareni, Gianni / Licata, Luana / Sacco, Francesca

    Genes. 2021 Mar. 22, v. 12, no. 3

    2021  

    Abstract: The coronavirus disease 2019 (COVID-19) pandemic has caused more than 2.3 million casualties worldwide and the lack of effective treatments is a major health concern. The development of targeted drugs is held back due to a limited understanding of the ... ...

    Abstract The coronavirus disease 2019 (COVID-19) pandemic has caused more than 2.3 million casualties worldwide and the lack of effective treatments is a major health concern. The development of targeted drugs is held back due to a limited understanding of the molecular mechanisms underlying the perturbation of cell physiology observed after viral infection. Recently, several approaches, aimed at identifying cellular proteins that may contribute to COVID-19 pathology, have been reported. Albeit valuable, this information offers limited mechanistic insight as these efforts have produced long lists of cellular proteins, the majority of which are not annotated to any cellular pathway. We have embarked in a project aimed at bridging this mechanistic gap by developing a new bioinformatic approach to estimate the functional distance between a subset of proteins and a list of pathways. A comprehensive literature search allowed us to annotate, in the SIGNOR 2.0 resource, causal information underlying the main molecular mechanisms through which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and related coronaviruses affect the host–cell physiology. Next, we developed a new strategy that enabled us to link SARS-CoV-2 interacting proteins to cellular phenotypes via paths of causal relationships. Remarkably, the extensive information about inhibitors of signaling proteins annotated in SIGNOR 2.0 makes it possible to formulate new potential therapeutic strategies. The proposed approach, which is generally applicable, generated a literature-based causal network that can be used as a framework to formulate informed mechanistic hypotheses on COVID-19 etiology and pathology.
    Schlagwörter COVID-19 infection ; Severe acute respiratory syndrome coronavirus 2 ; bioinformatics ; cell physiology ; etiology ; pandemic ; physiology ; therapeutics
    Sprache Englisch
    Erscheinungsverlauf 2021-0322
    Erscheinungsort Multidisciplinary Digital Publishing Institute
    Dokumenttyp Artikel
    Anmerkung NAL-AP-2-clean
    ZDB-ID 2527218-4
    ISSN 2073-4425
    ISSN 2073-4425
    DOI 10.3390/genes12030450
    Datenquelle NAL Katalog (AGRICOLA)

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  10. Artikel ; Online: The immunosuppressant drug azathioprine restrains adipogenesis of muscle Fibro/Adipogenic Progenitors from dystrophic mice by affecting AKT signaling.

    Reggio, Alessio / Spada, Filomena / Rosina, Marco / Massacci, Giorgia / Zuccotti, Alessandro / Fuoco, Claudia / Gargioli, Cesare / Castagnoli, Luisa / Cesareni, Gianni

    Scientific reports

    2019  Band 9, Heft 1, Seite(n) 4360

    Abstract: Fibro/Adipogenic Progenitors (FAPs) define a stem cell population playing a pro-regenerative role after muscle damage. When removed from their natural niche, FAPs readily differentiate into adipocytes or fibroblasts. This digressive differentiation ... ...

    Abstract Fibro/Adipogenic Progenitors (FAPs) define a stem cell population playing a pro-regenerative role after muscle damage. When removed from their natural niche, FAPs readily differentiate into adipocytes or fibroblasts. This digressive differentiation potential, which is kept under tight control in the healthy muscle niche, contributes to fat and scar infiltrations in degenerative myopathies, such as in Duchenne Muscular Dystrophy (DMD). Controlling FAP differentiation by means of small molecules may contribute to delay the adverse consequences of the progressive pathological degeneration while offering, at the same time, a wider temporal window for gene therapy and cell-based strategies. In a high content phenotypic screening, we identified the immunosuppressant, azathioprine (AZA) as a negative modulator of FAP adipogenesis. We show here that AZA negatively affects the adipogenic propensity of FAPs purified from wild type and mdx mice by impairing the expression of the master adipogenic regulator, peroxisome proliferator-activated receptor γ (PPARγ). We show that this inhibition correlates with a decline in the activation of the AKT-mTOR axis, the main pathway that transduces the pro-adipogenic stimulus triggered by insulin. In addition, AZA exerts a cytostatic effect that has a negative impact on the mitotic clonal process that is required for the terminal differentiation of the preadipocyte-committed cells.
    Mesh-Begriff(e) Adipogenesis/drug effects ; Animals ; Azathioprine/pharmacology ; Cell Differentiation/drug effects ; Cells, Cultured ; Disease Models, Animal ; Fibroblasts/drug effects ; Fibroblasts/metabolism ; Immunosuppressive Agents/pharmacology ; Mice ; Mice, Inbred mdx ; Models, Biological ; Muscular Dystrophy, Duchenne ; Myoblasts, Skeletal/drug effects ; Myoblasts, Skeletal/metabolism ; PPAR gamma ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction/drug effects ; Stem Cells/drug effects ; Stem Cells/metabolism ; TOR Serine-Threonine Kinases/metabolism
    Chemische Substanzen Immunosuppressive Agents ; PPAR gamma ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Azathioprine (MRK240IY2L)
    Sprache Englisch
    Erscheinungsdatum 2019-03-13
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-019-39538-y
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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