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  1. Article ; Online: The EXTREME Regimen Associating Cetuximab and Cisplatin Favors Head and Neck Cancer Cell Death and Immunogenicity with the Induction of an Anti-Cancer Immune Response.

    De Azevedo, Justine / Mourtada, Jana / Bour, Cyril / Devignot, Véronique / Schultz, Philippe / Borel, Christian / Pencreach, Erwan / Mellitzer, Georg / Gaiddon, Christian / Jung, Alain C

    Cells

    2022  Volume 11, Issue 18

    Abstract: 1) Background: The first line of treatment for recurrent/metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) has recently evolved with the approval of immunotherapies that target the anti-PD-1 immune checkpoint. However, only about 20% of the ... ...

    Abstract (1) Background: The first line of treatment for recurrent/metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) has recently evolved with the approval of immunotherapies that target the anti-PD-1 immune checkpoint. However, only about 20% of the patients display a long-lasting objective tumor response. The modulation of cancer cell immunogenicity via a treatment-induced immunogenic cell death is proposed to potentially be able to improve the rate of patients who respond to immune checkpoint blocking immunotherapies. (2) Methods: Using human HNSCC cell line models and a mouse oral cancer syngeneic model, we have analyzed the ability of the EXTREME regimen (combination therapy using the anti-EGFR cetuximab antibody and platinum-based chemotherapy) to modify the immunogenicity of HNSCC cells. (3) Results: We showed that the combination of cetuximab and cisplatin reduces cell growth through both cell cycle inhibition and the induction of apoptotic cell death independently of p53. In addition, different components of the EXTREME regimen were found to induce, to a variable extent, and in a cell-dependent manner, the emission of mediators of immunogenic cell death, including calreticulin, HMGB1, and type I Interferon-responsive chemokines. Interestingly, cetuximab alone or combined with the IC
    MeSH term(s) Animals ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Apoptosis ; Calreticulin ; Cetuximab/therapeutic use ; Cisplatin/therapeutic use ; HMGB1 Protein ; Head and Neck Neoplasms/drug therapy ; Head and Neck Neoplasms/immunology ; Humans ; Immunity ; Interferon Type I ; Mice ; Neoplasm Recurrence, Local/pathology ; Squamous Cell Carcinoma of Head and Neck/drug therapy ; Tumor Suppressor Protein p53
    Chemical Substances Calreticulin ; HMGB1 Protein ; Interferon Type I ; Tumor Suppressor Protein p53 ; Cetuximab (PQX0D8J21J) ; Cisplatin (Q20Q21Q62J)
    Language English
    Publishing date 2022-09-14
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells11182866
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Ultrasound and Transcriptomics Identify a Differential Impact of Cisplatin and Histone Deacetylation on Tumor Structure and Microenvironment in a Patient-Derived In Vivo Model of Gastric Cancer.

    Venkatasamy, Aina / Guerin, Eric / Blanchet, Anais / Orvain, Christophe / Devignot, Véronique / Jung, Matthieu / Jung, Alain C / Chenard, Marie-Pierre / Romain, Benoit / Gaiddon, Christian / Mellitzer, Georg

    Pharmaceutics

    2021  Volume 13, Issue 9

    Abstract: The reasons behind the poor efficacy of transition metal-based chemotherapies (e.g., cisplatin) or targeted therapies (e.g., histone deacetylase inhibitors, HDACi) on gastric cancer (GC) remain elusive and recent studies suggested that the tumor ... ...

    Abstract The reasons behind the poor efficacy of transition metal-based chemotherapies (e.g., cisplatin) or targeted therapies (e.g., histone deacetylase inhibitors, HDACi) on gastric cancer (GC) remain elusive and recent studies suggested that the tumor microenvironment could contribute to the resistance. Hence, our objective was to gain information on the impact of cisplatin and the pan-HDACi SAHA (suberanilohydroxamic acid) on the tumor substructure and microenvironment of GC, by establishing patient-derived xenografts of GC and a combination of ultrasound, immunohistochemistry, and transcriptomics to analyze. The tumors responded partially to SAHA and cisplatin. An ultrasound gave more accurate tumor measures than a caliper. Importantly, an ultrasound allowed a noninvasive real-time access to the tumor substructure, showing differences between cisplatin and SAHA. These differences were confirmed by immunohistochemistry and transcriptomic analyses of the tumor microenvironment, identifying specific cell type signatures and transcription factor activation. For instance, cisplatin induced an "epithelial cell like" signature while SAHA favored a "mesenchymal cell like" one. Altogether, an ultrasound allowed a precise follow-up of the tumor progression while enabling a noninvasive real-time access to the tumor substructure. Combined with transcriptomics, our results underline the different intra-tumoral structural changes caused by both drugs that impact differently on the tumor microenvironment.
    Language English
    Publishing date 2021-09-16
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527217-2
    ISSN 1999-4923
    ISSN 1999-4923
    DOI 10.3390/pharmaceutics13091485
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Specific serine-proline phosphorylation and glycogen synthase kinase 3β-directed subcellular targeting of stathmin 3/Sclip in neurons.

    Devaux, Sara / Poulain, Fabienne E / Devignot, Véronique / Lachkar, Sylvie / Irinopoulou, Theano / Sobel, André

    The Journal of biological chemistry

    2012  Volume 287, Issue 26, Page(s) 22341–22353

    Abstract: During nervous system development, neuronal growth, migration, and functional morphogenesis rely on the appropriate control of the subcellular cytoskeleton including microtubule dynamics. Stathmin family proteins play major roles during the various ... ...

    Abstract During nervous system development, neuronal growth, migration, and functional morphogenesis rely on the appropriate control of the subcellular cytoskeleton including microtubule dynamics. Stathmin family proteins play major roles during the various stages of neuronal differentiation, including axonal growth and branching, or dendritic development. We have shown previously that stathmins 2 (SCG10) and 3 (SCLIP) fulfill distinct, independent and complementary regulatory roles in axonal morphogenesis. Although the two proteins have been proposed to display the four conserved phosphorylation sites originally identified in stathmin 1, we show here that they possess distinct phosphorylation sites within their specific proline-rich domains (PRDs) that are differentially regulated by phosphorylation by proline-directed kinases involved in the control of neuronal differentiation. ERK2 or CDK5 phosphorylate the two proteins but with different site specificities. We also show for the first time that, unlike stathmin 2, stathmin 3 is a substrate for glycogen synthase kinase (GSK) 3β both in vitro and in vivo. Interestingly, stathmin 3 phosphorylated at its GSK-3β target site displays a specific subcellular localization at neuritic tips and within the actin-rich peripheral zone of the growth cone of differentiating hippocampal neurons in culture. Finally, pharmacological inhibition of GSK-3β induces a redistribution of stathmin 3, but not stathmin 2, from the periphery toward the Golgi region of neurons. Stathmin proteins can thus be either regulated locally or locally targeted by specific phosphorylation, each phosphoprotein of the stathmin family fulfilling distinct and specific roles in the control of neuronal differentiation.
    MeSH term(s) Animals ; Cell Differentiation ; Glycogen Synthase Kinase 3/metabolism ; Glycogen Synthase Kinase 3 beta ; HeLa Cells ; Humans ; Microtubules/metabolism ; Models, Biological ; Neurites/metabolism ; Neurons/metabolism ; Phosphorylation ; Proline/chemistry ; Rabbits ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; Serine/chemistry ; Stathmin/metabolism
    Chemical Substances Stathmin ; Serine (452VLY9402) ; Proline (9DLQ4CIU6V) ; GSK3B protein, human (EC 2.7.11.1) ; Glycogen Synthase Kinase 3 beta (EC 2.7.11.1) ; Gsk3b protein, rat (EC 2.7.11.1) ; Glycogen Synthase Kinase 3 (EC 2.7.11.26)
    Language English
    Publishing date 2012-05-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M112.344044
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uc I Zs.108: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: Subcellular Golgi localization of stathmin family proteins is promoted by a specific set of DHHC palmitoyl transferases.

    Levy, Aurore D / Devignot, Véronique / Fukata, Yuko / Fukata, Masaki / Sobel, André / Chauvin, Stéphanie

    Molecular biology of the cell

    2011  Volume 22, Issue 11, Page(s) 1930–1942

    Abstract: Protein palmitoylation is a reversible lipid modification that plays critical roles in protein sorting and targeting to specific cellular compartments. The neuronal microtubule-regulatory phosphoproteins of the stathmin family (SCG10/stathmin 2, SCLIP/ ... ...

    Abstract Protein palmitoylation is a reversible lipid modification that plays critical roles in protein sorting and targeting to specific cellular compartments. The neuronal microtubule-regulatory phosphoproteins of the stathmin family (SCG10/stathmin 2, SCLIP/stathmin 3, and RB3/stathmin 4) are peripheral proteins that fulfill specific and complementary roles in the formation and maturation of the nervous system. All neuronal stathmins are localized at the Golgi complex and at vesicles along axons and dendrites. Their membrane anchoring results from palmitoylation of two close cysteine residues present within their homologous N-terminal targeting domains. By preventing palmitoylation with 2-bromopalmitate or disrupting the integrity of the Golgi with brefeldin A, we were able to show that palmitoylation of stathmins 2 and 3 likely occurs at the Golgi and is crucial for their specific subcellular localization and trafficking. In addition, this membrane binding is promoted by a specific set of palmitoyl transferases that localize with stathmins 2 and 3 at the Golgi, directly interact with them, and enhance their membrane association. The subcellular membrane-associated microtubule-regulatory activity of stathmins might then be fine-tuned by extracellular stimuli controlling their reversible palmitoylation, which can be viewed as a crucial regulatory process for specific and local functions of stathmins in neurons.
    MeSH term(s) Acyltransferases/metabolism ; Animals ; Brefeldin A/pharmacology ; Cell Membrane/metabolism ; Cells, Cultured ; Fluorescent Antibody Technique, Indirect ; Golgi Apparatus/drug effects ; Golgi Apparatus/metabolism ; Hippocampus/cytology ; Hippocampus/metabolism ; Humans ; Lipoylation/drug effects ; Neurons/metabolism ; Palmitates/pharmacology ; Protein Processing, Post-Translational/drug effects ; Protein Transport ; Rats ; Stathmin/metabolism
    Chemical Substances Palmitates ; Stathmin ; 2-bromopalmitate (18263-25-7) ; Brefeldin A (20350-15-6) ; Acyltransferases (EC 2.3.-)
    Language English
    Publishing date 2011-04-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1098979-1
    ISSN 1939-4586 ; 1059-1524
    ISSN (online) 1939-4586
    ISSN 1059-1524
    DOI 10.1091/mbc.E10-10-0824
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2853: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MO 410: Show issues

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  5. Article ; Online: Transcriptional activator TAp63 is upregulated in muscular atrophy during ALS and induces the pro-atrophic ubiquitin ligase Trim63.

    von Grabowiecki, Yannick / Abreu, Paula / Blanchard, Orphee / Palamiuc, Lavinia / Benosman, Samir / Mériaux, Sophie / Devignot, Véronique / Gross, Isabelle / Mellitzer, Georg / Gonzalez de Aguilar, José L / Gaiddon, Christian

    eLife

    2016  Volume 5

    Abstract: Mechanisms of muscle atrophy are complex and their understanding might help finding therapeutic solutions for pathologies such as amyotrophic lateral sclerosis (ALS). We meta-analyzed transcriptomic experiments of muscles of ALS patients and mouse models, ...

    Abstract Mechanisms of muscle atrophy are complex and their understanding might help finding therapeutic solutions for pathologies such as amyotrophic lateral sclerosis (ALS). We meta-analyzed transcriptomic experiments of muscles of ALS patients and mouse models, uncovering a p53 deregulation as common denominator. We then characterized the induction of several p53 family members (p53, p63, p73) and a correlation between the levels of p53 family target genes and the severity of muscle atrophy in ALS patients and mice. In particular, we observed increased p63 protein levels in the fibers of atrophic muscles via denervation-dependent and -independent mechanisms. At a functional level, we demonstrated that TAp63 and p53 transactivate the promoter and increased the expression of Trim63 (MuRF1), an effector of muscle atrophy. Altogether, these results suggest a novel function for p63 as a contributor to muscular atrophic processes via the regulation of multiple genes, including the muscle atrophy gene Trim63.
    MeSH term(s) Amyotrophic Lateral Sclerosis/physiopathology ; Animals ; Disease Models, Animal ; Gene Expression Profiling ; Humans ; Mice ; Muscle Proteins/biosynthesis ; Muscles/pathology ; Transcription Factors/biosynthesis ; Tripartite Motif Proteins ; Tumor Suppressor Protein p53/biosynthesis ; Tumor Suppressor Proteins/biosynthesis ; Ubiquitin-Protein Ligases/biosynthesis ; Up-Regulation
    Chemical Substances Muscle Proteins ; TP63 protein, human ; Transcription Factors ; Tripartite Motif Proteins ; Tumor Suppressor Protein p53 ; Tumor Suppressor Proteins ; TRIM63 protein, human (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2016-02-26
    Publishing country England
    Document type Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.10528
    Database MEDical Literature Analysis and Retrieval System OnLINE

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