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Article ; Online: The needle and the haystack: single molecule tracking to probe the transcription factor search in eukaryotes.

Mazzocca, Matteo / Fillot, Tom / Loffreda, Alessia / Gnani, Daniela / Mazza, Davide

2021 Volume 49, Issue 3, Page(s) 1121–1132

Abstract: Transcription factors (TFs) regulate transcription of their target genes by identifying and binding to regulatory regions of the genome among billions of potential non-specific decoy sites, a task that is often presented as a 'needle in the haystack' ... ...

Abstract	Transcription factors (TFs) regulate transcription of their target genes by identifying and binding to regulatory regions of the genome among billions of potential non-specific decoy sites, a task that is often presented as a 'needle in the haystack' challenge. The TF search process is now well understood in bacteria, but its characterization in eukaryotes needs to account for the complex organization of the nuclear environment. Here we review how live-cell single molecule tracking is starting to shed light on the TF search mechanism in the eukaryotic cell and we outline the future challenges to tackle in order to understand how nuclear organization modulates the TF search process in physiological and pathological conditions.
MeSH term(s)	Animals ; Binding Sites/genetics ; Cell Nucleus/genetics ; Cell Nucleus/metabolism ; Eukaryota/genetics ; Eukaryota/metabolism ; Gene Expression Regulation ; Genome/genetics ; Humans ; Protein Binding ; Regulatory Sequences, Nucleic Acid/genetics ; Single Molecule Imaging/methods ; Transcription Factors/metabolism
Chemical Substances	Transcription Factors
Language	English
Publishing date	2021-05-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	184237-7
ISSN	1470-8752 ; 0300-5127
ISSN (online)	1470-8752
ISSN	0300-5127
DOI	10.1042/BST20200709
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Epigenetic Therapies for Acute Myeloid Leukemia and Their Immune-Related Effects.

Gambacorta, Valentina / Gnani, Daniela / Vago, Luca / Di Micco, Raffaella

Frontiers in cell and developmental biology

2019 Volume 7, Page(s) 207

Abstract: Over the past decades, our molecular understanding of acute myeloid leukemia (AML) pathogenesis dramatically increased, thanks also to the advent of next-generation sequencing (NGS) technologies. Many of these findings, however, have not yet translated ... ...

Abstract	Over the past decades, our molecular understanding of acute myeloid leukemia (AML) pathogenesis dramatically increased, thanks also to the advent of next-generation sequencing (NGS) technologies. Many of these findings, however, have not yet translated into new prognostic markers or rationales for treatments. We now know that AML is a highly heterogeneous disease characterized by a very low mutational burden. Interestingly, the few mutations identified mainly reside in epigenetic regulators, which shape and define leukemic cell identity. In the light of these discoveries and given the increasing number of drugs targeting epigenetic regulators in clinical development and testing, great interest is emerging for the use of small molecules targeting leukemia epigenome. Together with their effects on leukemia cell-intrinsic properties, such as proliferation and survival, epigenetic drugs may affect the way leukemic cells communicate with the surrounding components of the tumor and immune microenvironment. Here, we review current knowledge on alterations in the AML epigenetic landscape and discuss the promises of epigenetic therapies for AML treatment. Finally, we summarize emerging molecular studies elucidating how epigenetic rewiring in cancer cells may as well exert immune-modulatory functions, boost the immune system, and potentially contribute to better patient outcomes.
Language	English
Publishing date	2019-10-11
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2019.00207
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Article ; Online: Chromatin organization drives the search mechanism of nuclear factors.

Mazzocca, Matteo / Loffreda, Alessia / Colombo, Emanuele / Fillot, Tom / Gnani, Daniela / Falletta, Paola / Monteleone, Emanuele / Capozi, Serena / Bertrand, Edouard / Legube, Gaelle / Lavagnino, Zeno / Tacchetti, Carlo / Mazza, Davide

Nature communications

2023 Volume 14, Issue 1, Page(s) 6433

Abstract: Nuclear factors rapidly scan the genome for their targets, but the role of nuclear organization in such search is uncharted. Here we analyzed how multiple factors explore chromatin, combining live-cell single-molecule tracking with multifocal structured ... ...

Abstract	Nuclear factors rapidly scan the genome for their targets, but the role of nuclear organization in such search is uncharted. Here we analyzed how multiple factors explore chromatin, combining live-cell single-molecule tracking with multifocal structured illumination of DNA density. We find that factors displaying higher bound fractions sample DNA-dense regions more exhaustively. Focusing on the tumor-suppressor p53, we demonstrate that it searches for targets by alternating between rapid diffusion in the interchromatin compartment and compact sampling of chromatin dense regions. Efficient targeting requires balanced interactions with chromatin: fusing p53 with an exogenous intrinsically disordered region potentiates p53-mediated target gene activation at low concentrations, but leads to condensates at higher levels, derailing its search and downregulating transcription. Our findings highlight the role of disordered regions on factors search and showcase a powerful method to generate traffic maps of the eukaryotic nucleus to dissect how its organization guides nuclear factors action.
MeSH term(s)	Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Chromatin/genetics ; Chromatin/metabolism ; DNA/metabolism ; Chromosomes/metabolism ; Transcriptional Activation ; Cell Nucleus/genetics ; Cell Nucleus/metabolism
Chemical Substances	Tumor Suppressor Protein p53 ; Chromatin ; DNA (9007-49-2)
Language	English
Publishing date	2023-10-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-42133-5
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Epigenetic Therapies for Acute Myeloid Leukemia and Their Immune-Related Effects

Valentina Gambacorta / Daniela Gnani / Luca Vago / Raffaella Di Micco

Frontiers in Cell and Developmental Biology, Vol

2019 Volume 7

Abstract	Over the past decades, our molecular understanding of acute myeloid leukemia (AML) pathogenesis dramatically increased, thanks also to the advent of next-generation sequencing (NGS) technologies. Many of these findings, however, have not yet translated into new prognostic markers or rationales for treatments. We now know that AML is a highly heterogeneous disease characterized by a very low mutational burden. Interestingly, the few mutations identified mainly reside in epigenetic regulators, which shape and define leukemic cell identity. In the light of these discoveries and given the increasing number of drugs targeting epigenetic regulators in clinical development and testing, great interest is emerging for the use of small molecules targeting leukemia epigenome. Together with their effects on leukemia cell-intrinsic properties, such as proliferation and survival, epigenetic drugs may affect the way leukemic cells communicate with the surrounding components of the tumor and immune microenvironment. Here, we review current knowledge on alterations in the AML epigenetic landscape and discuss the promises of epigenetic therapies for AML treatment. Finally, we summarize emerging molecular studies elucidating how epigenetic rewiring in cancer cells may as well exert immune-modulatory functions, boost the immune system, and potentially contribute to better patient outcomes.
Keywords	acute myeloid leukemia ; epigenetics ; therapy ; immune activation ; chromatin ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2019-10-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Focal Adhesion Kinase: Insight into Molecular Roles and Functions in Hepatocellular Carcinoma.

Panera, Nadia / Crudele, Annalisa / Romito, Ilaria / Gnani, Daniela / Alisi, Anna

International journal of molecular sciences

2017 Volume 18, Issue 1

Abstract: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Due to the high incidence of post-operative recurrence after current treatments, the identification of new and more effective drugs is required. In previous ... ...

Abstract	Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Due to the high incidence of post-operative recurrence after current treatments, the identification of new and more effective drugs is required. In previous years, new targetable genes/pathways involved in HCC pathogenesis have been discovered through the help of high-throughput sequencing technologies. Mutations in
MeSH term(s)	Carcinoma, Hepatocellular/enzymology ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/pathology ; Disease Progression ; Focal Adhesion Protein-Tyrosine Kinases/genetics ; Focal Adhesion Protein-Tyrosine Kinases/metabolism ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Neoplastic ; Humans ; Liver Neoplasms/enzymology ; Liver Neoplasms/genetics ; Liver Neoplasms/pathology ; Models, Genetic ; Neoplasm Invasiveness ; Neoplastic Stem Cells/metabolism
Chemical Substances	Focal Adhesion Protein-Tyrosine Kinases (EC 2.7.10.2)
Language	English
Publishing date	2017-01-05
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms18010099
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Integrated Multiomic Profiling Identifies the Epigenetic Regulator PRC2 as a Therapeutic Target to Counteract Leukemia Immune Escape and Relapse.

Gambacorta, Valentina / Beretta, Stefano / Ciccimarra, Martina / Zito, Laura / Giannetti, Kety / Andrisani, Angela / Gnani, Daniela / Zanotti, Lucia / Oliveira, Giacomo / Carrabba, Matteo Giovanni / Cittaro, Davide / Merelli, Ivan / Ciceri, Fabio / Di Micco, Raffaella / Vago, Luca

Cancer discovery

2022 Volume 12, Issue 6, Page(s) 1449–1461

Abstract: Immune escape represents a major driver of acute myeloid leukemia (AML) reemergence after allogeneic hematopoietic cell transplantation (allo-HCT), with up to 40% of relapses prompted by nongenomic loss of HLA class II expression in leukemia cells. By ... ...

Abstract	Immune escape represents a major driver of acute myeloid leukemia (AML) reemergence after allogeneic hematopoietic cell transplantation (allo-HCT), with up to 40% of relapses prompted by nongenomic loss of HLA class II expression in leukemia cells. By integrative analysis of gene expression, DNA methylation, and chromatin accessibility in paired diagnosis/relapse primary samples and in the respective patient-derived xenografts (PDX), we identify the polycomb repressive complex 2 (PRC2) as a key epigenetic driver of this immune escape modality. We report that loss of expression of HLA class II molecules is accompanied by a PRC2-dependent reduction in chromatin accessibility. Pharmacologic inhibition of PRC2 subunits rescues HLA class II expression in AML relapses in vitro and in vivo, with consequent recovery of leukemia recognition by CD4+ T cells. Our results uncover a novel link between epigenetics and leukemia immune escape, which may rapidly translate into innovative strategies to cure or prevent AML posttransplantation relapse. Significance: Loss of HLA class II expression represents a frequent mechanism of leukemia posttransplantation relapse. Here we identify PRC2 as the main epigenetic driver of this immune escape modality and show that its chemical inhibition can reinstate a proficient graft-versus-leukemia effect, providing an innovative rationale for personalized epigenetic immunotherapies. See related commentary by Köhler and Zeiser, p. 1410. This article is highlighted in the In This Issue feature, p. 1397.
MeSH term(s)	Chromatin/genetics ; Chromatin/immunology ; Epigenesis, Genetic ; Hematopoietic Stem Cell Transplantation ; Histocompatibility Antigens Class II/biosynthesis ; Histocompatibility Antigens Class II/genetics ; Histocompatibility Antigens Class II/immunology ; Humans ; Leukemia, Myeloid, Acute/immunology ; Leukemia, Myeloid, Acute/therapy ; Polycomb Repressive Complex 2/genetics ; Polycomb Repressive Complex 2/immunology ; Recurrence ; Tumor Escape/genetics
Chemical Substances	Chromatin ; Histocompatibility Antigens Class II ; Polycomb Repressive Complex 2 (EC 2.1.1.43)
Language	English
Publishing date	2022-03-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	2625242-9
ISSN	2159-8290 ; 2159-8274
ISSN (online)	2159-8290
ISSN	2159-8274
DOI	10.1158/2159-8290.CD-21-0980
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Article ; Online: Human iPSC-based neurodevelopmental models of globoid cell leukodystrophy uncover patient- and cell type-specific disease phenotypes.

Mangiameli, Elisabeth / Cecchele, Anna / Morena, Francesco / Sanvito, Francesca / Matafora, Vittoria / Cattaneo, Angela / Della Volpe, Lucrezia / Gnani, Daniela / Paulis, Marianna / Susani, Lucia / Martino, Sabata / Di Micco, Raffaella / Bachi, Angela / Gritti, Angela

Stem cell reports

2021 Volume 16, Issue 6, Page(s) 1478–1495

Abstract: Globoid cell leukodystrophy (GLD) is a rare neurodegenerative lysosomal storage disease caused by an inherited deficiency of β-galactocerebrosidase (GALC). GLD pathogenesis and therapeutic correction have been poorly studied in patient neural cells. Here, ...

Abstract	Globoid cell leukodystrophy (GLD) is a rare neurodegenerative lysosomal storage disease caused by an inherited deficiency of β-galactocerebrosidase (GALC). GLD pathogenesis and therapeutic correction have been poorly studied in patient neural cells. Here, we investigated the impact of GALC deficiency and lentiviral vector-mediated GALC rescue/overexpression in induced pluripotent stem cell (iPSC)-derived neural progenitors and neuronal/glial progeny obtained from two GLD patients. GLD neural progeny displayed progressive psychosine storage, oligodendroglial and neuronal defects, unbalanced lipid composition, and early activation of cellular senescence, depending on the disease-causing mutation. The partial rescue of the neural differentiation program upon GALC reconstitution and psychosine clearance suggests multiple mechanisms contributing to neural pathology in GLD. Also, the pathological phenotype associated to supraphysiological GALC levels highlights the need of regulated GALC expression for proper human neural commitment/differentiation. These data have important implications for establishing safe therapeutic strategies to enhance disease correction of GLD.
MeSH term(s)	Cell Differentiation ; Cells, Cultured ; Galactosylceramidase/genetics ; Galactosylceramidase/metabolism ; Genetic Predisposition to Disease ; Genetic Therapy/methods ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Leukodystrophy, Globoid Cell/genetics ; Leukodystrophy, Globoid Cell/metabolism ; Oligodendroglia/metabolism ; Phenotype ; Psychosine/metabolism ; Stem Cells/metabolism
Chemical Substances	Psychosine (2238-90-6) ; Galactosylceramidase (EC 3.2.1.46)
Language	English
Publishing date	2021-05-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2720528-9
ISSN	2213-6711 ; 2213-6711
ISSN (online)	2213-6711
ISSN	2213-6711
DOI	10.1016/j.stemcr.2021.04.011
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Article ; Online: Focal Adhesion Kinase

Nadia Panera / Annalisa Crudele / Ilaria Romito / Daniela Gnani / Anna Alisi

International Journal of Molecular Sciences, Vol 18, Iss 1, p

Insight into Molecular Roles and Functions in Hepatocellular Carcinoma

2017 Volume 99

Abstract	Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Due to the high incidence of post-operative recurrence after current treatments, the identification of new and more effective drugs is required. In previous years, new targetable genes/pathways involved in HCC pathogenesis have been discovered through the help of high-throughput sequencing technologies. Mutations in TP53 and β-catenin genes are the most frequent aberrations in HCC. However, approaches able to reverse the effect of these mutations might be unpredictable. In fact, if the reactivation of proteins, such as p53 in tumours, holds great promise as anticancer therapy, there are studies arguing that chronic activation of these types of molecules may be deleterious. Thus, recently the efforts on potential targets have focused on actionable mutations, such as those occurring in the gene encoding for focal adhesion kinase (FAK). This tyrosine kinase, localized to cellular focal contacts, is over-expressed in a variety of human tumours, including HCC. Moreover, several lines of evidence demonstrated that FAK depletion or inhibition impair in vitro and in vivo HCC growth and metastasis. Here, we provide an overview of FAK expression and activity in the context of tumour biology, discussing the current evidence of its connection with HCC development and progression.
Keywords	focal adhesion kinase ; hepatocellular carcinoma ; cancer stem cells ; proliferation ; metastasis ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	616
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Dual role of microRNAs in NAFLD.

Ceccarelli, Sara / Panera, Nadia / Gnani, Daniela / Nobili, Valerio

International journal of molecular sciences

2013 Volume 14, Issue 4, Page(s) 8437–8455

Abstract: MicroRNAs are important post-transcriptional regulators in different pathophysiological processes. They typically affect the mRNA stability or translation finally leading to the repression of target gene expression. Notably, it is thought that microRNAs ... ...

Abstract	MicroRNAs are important post-transcriptional regulators in different pathophysiological processes. They typically affect the mRNA stability or translation finally leading to the repression of target gene expression. Notably, it is thought that microRNAs are crucial for regulating gene expression during metabolic-related disorders, such as nonalcoholic fatty liver disease (NAFLD). Several studies identify specific microRNA expression profiles associated to different histological features of NAFLD, both in animal models and in patients. Therefore, specific assortments of certain microRNAs could have enormous diagnostic potentiality. In addition, microRNAs have also emerged as possible therapeutic targets for the treatment of NAFLD-related liver damage. In this review, we discuss the experimental evidence about microRNAs both as potential non-invasive early diagnostic markers and as novel therapeutic targets in NAFLD and its more severe liver complications.
MeSH term(s)	Animals ; Disease Models, Animal ; Gene Expression Profiling ; Humans ; Lipid Metabolism/genetics ; Liver Cirrhosis/etiology ; Liver Cirrhosis/genetics ; Liver Cirrhosis/metabolism ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Non-alcoholic Fatty Liver Disease/etiology ; Non-alcoholic Fatty Liver Disease/genetics ; Non-alcoholic Fatty Liver Disease/metabolism
Chemical Substances	MicroRNAs
Language	English
Publishing date	2013-04-17
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1661-6596
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms14048437
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Article ; Online: Correction to: Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects.

Journal of experimental & clinical cancer research : CR

2022 Volume 41, Issue 1, Page(s) 40

Language	English
Publishing date	2022-01-27
Publishing country	England
Document type	Published Erratum
ZDB-ID	803138-1
ISSN	1756-9966 ; 0392-9078
ISSN (online)	1756-9966
ISSN	0392-9078
DOI	10.1186/s13046-022-02247-y
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