117,940 research outputs found
Mario Menin. camicia nera futurista e primo battaglista del mondo
No full textMario Menin : camicia nera futurista e primo battaglista del mondo / (presentazione di Filippo Tommaso Marinetti e Luigi Scrivo). - Roma : Edizioni futuriste di poesia, stampa 1941
Dedica manoscritta dell\u27autore: A Bodrero Emilio / con ammirazione / Mario Menin / Bodoni 96 / Roma
https://galileodiscovery.unipd.it/discovery/fulldisplay?context=L&vid=39UPD_INST:VU1&search_scope=MyInst_and_CI&tab=Everything&docid=alma99000150748020604
Targeting the MLL complex in acute leukemia
No full textChromosomal rearrangements leading mostly to fusion oncoproteins of the Mixed Lineage Leukemia (MLL) gene occur in about 10% of all patients with acute leukemia and are often associated with poor clinical outcome, emphasizing the need for new treatment modalities. The MLL protein forms a ternary complex with the lens epithelium-derived growth factor (LEDGF/p75 also known as PSIP1) and another protein MENIN. Previous work has shown that LEDGF/p75 contributes to the association of the MLL multi-protein complex to chromatin. In addition, LEDGF/p75 is known for acting as a tether of the human immunodeficiency virus 1 (HIV-1) pre-integration complex to chromatin, and previous works has demonstrated that expression of the C-terminal fragment fused to eGFP (eGFP-LEDGF/p75325-530) impaired HIV-1 replication. Here, we explored this strategy to selectively interfere with the leukemogenic activity of MLL-fusion proteins. We found that expression of the LEDGF/p75325-530 fragment impaired the clonogenic growth of MLL-fusion gene transformed human and mouse leukemic cell lines, without affecting the growth of immortalized control cells, or normal lineage marker-depleted murine bone marrow cells. Expression of LEDGF/p75325-530 was associated with downregulation of the known MLL target Hoxa9 and associated with impaired cell cycle progression. Structure-function analysis revealed two small eGFP fused LEDGF/p75 peptide-sized fragments, LEDGF/p75424-435 and LEDGF/p75375-386 were able to phenocopy these effects. LEDGF/p75325-530 and the smaller active peptides were all able to disrupt the LEDGF/p75-MLL interaction. Expression of LEDGF/p75325-530 or the LEDGF/p75375-386 fragment increased the latency period to disease development in vivo in a mouse bone marrow transplant model of MLL-AF9 induced acute myeloid leukemia (AML). From these studies we concluded that small peptides disrupting the LEDGF/p75-MLL interface have selective anti-leukemic activity providing a direct rationale for the design of small molecule inhibitors targeting this interaction.
Intensive biochemical and structural analysis led by our collaborators (J. De Rijck, K. Cermakova, KU LEUVEN, Belgium) further allowed the identification of two MLL-LEDGF/p75 targetable interfaces. Indeed a recently resolved partial structure revealed a potentially drugable hydrophobic pocked stabilizing the MLL-MENIN-LEDGF/p75 interface. Interestingly, our IBD-derived LEDGF/p75424-435 fragment was targeting this interface that seems to be dependent on the interaction with MENIN and has been
successfully targeted by MENIN small molecule inhibitors. As the available X-ray data represented only a partial structure of the LEDGF/p75-MLL-MENIN complex, our collaborators used NMR spectroscopy to identify an additional MLL-LEDGF/p75 interface, which partially overlaps with the binding site of known LEDGF/p75 interactors including the HIV-1 integrase. They proved that binding of the HIV-1 integrase or MLL to LEDGF/p75 is mutually exclusive and seems to be dependent of MENIN. Importantly, the newly defined interface was directly targeted by expression of the LEDGF/p75375-386 IBD-derived fragment we previously defined. We were then able to show that the clonogenic growth of primary murine MLL-AF9 expressing leukemic blasts was selectively impaired upon overexpression of a LEDGF/p75 binding cyclic peptide CP65, known to bind the IBD and disrupt its interaction with HIV-1 integrase. Thus collectively our data shows that this newly defined protein-protein interface represents a new target for the development of therapeutics against HIV-1 replication as well as LEDGF/p75-dependent MLL fusion oncoprotein driven leukemic disorders.
Intensive research efforts led by many groups resulted in the definition of multiple possibilities for potential interference with the leukemogenic MLL fusion protein complex. We therefore also started to explore whether targeting of the MLL complex at different nodes could result in synergistic effects to efficiently impair MLL-fusion mediated leukemia. Previous studies have shown that the histone H3 lysine 79 (H3K79) methyltransferase DOT1L is essential for MLL-fusion driven leukemogenesis. Selective small molecule DOT1L inhibitors have been generated and are currently entering first clinical trials. However, when given in monotherapy, work in mouse models has shown limited and slow responses to these compounds in many MLL-rearranged leukemia models. Collaborators from the Novartis Institute for Biomedical Research (NIBR, Basel) have performed shRNA screens in MLL-rearranged cell lines to identify sensitizing targets for DOT1L inhibitors and found that knockdown of several MLL complex components, including LEDGF/p75 significantly enhanced anti-leukemic responses. In absence of any available pharmacological agents targeting LEDGF/p75, they decided to test syngertistic activity of the DOT1L inhibitor EPZ004777 in combination with the MENIN inhibitor MI-2-2 previously shown to induce growth arrest and differentiation in MLL-rearranged leukemia cells. We therefore tested the effects of combination of MI-2-2 and EPZ004777 in our MLL-AF9 mouse AML model and found that transient and non-lethal exposure to the combination of these compounds was sufficient to permanently disable their leukemogenic infiltrating
potential in vivo mainly through induction of a rapid and effective differentiation of MLL-AF9 expressing leukemic blasts. Altogether, these results suggested that the EPZ004777/MI-2-2 combination might deliver synergistic and durable anti-leukemia effects in MLL-rearranged AML.
All together this work suggests that the MENIN-MLL-LEDGF/p75 complex offers several interfaces for selective therapeutic targeting for MLL-rerranged acute leukemia. In addition, our results suggest that co-targeting the MLL complex at different nodes could pave the way for selective and efficient novel therapeutic approaches for leukemic disorders mediated by MLL fusion oncoproteins. Such approaches need to be clinically tested in particular whether they will be able to overcome early relapse of the disease that is the “Achilles heel” of current applied polychemotherapeutic strategies
Differential expression of menin in sporadic pituitary adenomas
No full textPituitary adenomas represent one of the key features of multiple endocrine neoplasia type 1. The gene involved in this syndrome (MEN1) is a putative tumor suppressor, that codes for a 610-amino acid nuclear protein termed 'menin'. Analyses of sporadic pituitary adenomas have so far failed to reveal MEN1 mutations or defects in MEN1 transcription in these tumors. In the present study we detected menin protein expression in a panel of normal and tumoral pituitary tissues, using a monoclonal antibody against the carboxy-terminus of menin. In the normal human pituitary gland, strong nuclear staining for menin was detectable in the majority of the endocrine cells of the anterior lobe, without a clear association with a particular hormone-producing type. In sporadic pituitary adenomas, menin expression was variable, with a high percentage of cases demonstrating a significant decrease in menin immunoreactivity when compared with the normal pituitary. Interestingly, metastatic tissues derived from one pituitary carcinoma had no detectable menin levels. Altogether, our data provide the first information regarding the status of menin expression in human normal and neoplastic pituitary as determined by immunohistochemistry (IHC)
Menin (un nouvel acteur dans le cycle cellulaire ?)
No full textLa NEM1 est un syndrome cancéreux affectant de nombreuses glandes endocrines, qui résulte d une prédisposition génétique liée à des mutations du gène MEN1. La Menin, protéine codée par MEN1 possède de nombreux partenaires qui interviennent dans la dynamique de la chromatine, la régulation de la transcription et de la stabilité du génome. Le besoin de mieux connaître les fonctions biochimiques de la Menin m a conduit à tenter de produire la protéine purifiée en grande quantité. Ce faisant, j ai pu apporter des informations sur la structure de la Menin. Sur un plan fonctionnel, j ai étudié l interaction entre Menin et l oncosuppresseur p53, et montré que certaines modifications post-traductionnelles de p53 déterminantes pour son activité et sa stabilité en réponse à un stress génotoxique, n affectent pas l interaction, rendant possible que ce soient des modifications de la Menin qui y jouent un rôle déterminant. J ai ainsi montré que la Menin pouvait être mono-ubiquitinée. La Menin interfère également avec un autre régulateur du cycle cellulaire, la protéine RB dont elle semble réguler le niveau de phosphorylation et peut-être même la quantité totale dans la cellule.MEN1 is a cancer syndrome affecting many endocrine glands, which results from a genetic predisposition related to mutations of the MEN1 gene. Menin, the protein encoded by MEN1 has many partners that play a role in the dynamics of chromatin and in the regulation of the transcription and of genome stability. The need for knowing better the biochemical functions of Menin led me to try to produce the purified protein in great quantity. By doing this, I could bring information on the structure of Menin. On a functional level, I studied the interaction between Menin and the oncosuppressor p53, and showed that certain post-translational modifications of p53 crucial for its activity and its stability in response to a genotoxic stress, do not affect the interaction, making possible that modifications of Menin play a determining role there. I thus showed that Menin could be monoubiquitinylated. Menin also interferes with another regulator of the cell cycle, the protein RB of which it seems to control the level of phosphorylation and perhaps even the total amount in the cell.TOURS-Bibl.électronique (372610011) / SudocSudocFranceF
FIGURE 6 from Clinically Defined Mutations in <i>MEN1</i> Alter Its Tumor-suppressive Function Through Increased Menin Turnover
No full textClinical MEN1 mutations and variants reduce the ability of menin to repress gastrin gene expression. Gastrin transcript levels (GAST) in AGS (A), MKN-45G (B), and BON-1 (C) cells following overexpression with empty vector (pcDNA), wild-type menin, and the three menin mutants. GAST mRNA was normalized to HPRT1 expression and reported as fold-change relative to pcDNA control. D, Expression of MEN1 mRNA in BON-1 cells. *, P P P P post hoc test; mean ± SEM. E, Relative GAST mRNA expression in AGS cells overexpressing menin plasmids and following serum starvation and treatment with EGF (16 hours, 40 nmol/L). F, The GasLuc system was used to evaluate human gastrin promoter activity following overexpression of empty vector (pcDNA), GasLuc plasmid alone, or GasLuc plasmid in the presence of wild-type menin and the three mutants and EGF (16 hours, 40 nmol/L). Firefly luciferase activity was normalized to the Renilla-Luciferase co-reporter. ***, P post hoc test; mean ± SEM. Relative GAST mRNA expression in BON-1 (G) and GLUTag (H) cells overexpressing menin plasmids and following serum starvation and treatment with EGF (16 hours, 40 nmol/L). I, Immunofluorescent staining of FLAG-menin expression in GLUTag cells in the presence or absence of EGF (8 hours, 40 nmol/L) and MG132 (10 μmol/L). NT = no treatment control. J, Quantitation of FLAG-menin expression in nuclear and cytoplasmic compartments from immunofluorescence-stained images. Counts were obtained from 10 random HPF images. **, P post hoc test; mean ± SEM. WT, wild-type.</p
Rilevamento 3D di elementi murari antichi del Teatro Romano di Verona per il progetto di consolidamento statico.
No full textApplicazione della tecnica di modellazione tridimensionale con strumentazione laser scanner nella disciplina dell’architettura e del restauro. Acquisizione, editing, post-processing e restituzione di alcuni elementi rappresentativi del complesso monumentale del Teatro Romano di Verona
Apoptosis signalling pathways in the compound ascidian Botryllus schlosseri during the blastogenetic cycle.
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Shadows of slavery: refractions of the past, challenges of the present
No full textBetween 2014 and 2018, under the auspices of the ERC grant ‘Shadows
of Slavery in West Africa and Beyond (SWAB): a Historical Anthropology’
(Grant Agreement: 313737), a group of anthropologists directed
by Alice Bellagamba investigated the shadows of slavery, and their specific
ethnographic manifestations, in Africa and beyond. The results ‘descend’ into the everyday worlds of people
who live the consequences of historical slave systems or who happen
to find themselves ‘trapped’ in novel forms of socio-political inequality,
racism, labour exploitation and sexual and moral violence. We seek
to interrogate their stories in ways respectful of histories and contexts.
Often, discussions on the continuities/discontinuities between ‘old’ and
‘modern’ slavery end up being constrained by terminological disputes,
as if terminological clarification may clear consciences of the disquieting
similarities (and differences) between yesterday’s slave systems and today’s
examples of dehumanisation, indignity and exploitation
Applicazione delle metodologie geo-topografiche satellitari per lo studio di modelli matematici del geoide in ambito locale.
No full textUniversità di Padova, Dipartimento di Architettura, Urbanistica e Rilevamento
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