ErbB3-ErbB2 Complexes as a Therapeutic Target in a Subset of Wild-type BRAF/NRAS Cutaneous Melanomas.

The treatment options remain limited for patients with melanoma who are wild-type for both BRAF and NRAS (WT/WT). We demonstrate that a subgroup of WT/WT melanomas display high basal phosphorylation of ErbB3 that is associated with autocrine production of the ErbB3 ligand neuregulin-1 (NRG1). In WT/WT melanoma cells displaying high levels of phospho-ErbB3, knockdown of NRG1 reduced cell viability and was associated with decreased phosphorylation of ErbB3, its coreceptor ErbB2, and its downstream target, AKT. Similar effects were observed by targeting ErbB3 with either siRNAs or the neutralizing ErbB3 monoclonal antibodies huHER3-8 and NG33. In addition, pertuzumab-mediated inhibition of ErbB2 heterodimerization decreased AKT phosphorylation, cell growth in vitro, and xenograft growth in vivo. Pertuzumab also potentiated the effects of MEK inhibitor on WT/WT melanoma growth in vitro and in vivo. These findings demonstrate that targeting ErbB3-ErbB2 signaling in a cohort of WT/WT melanomas leads to tumor growth reduction. Together, these studies support the rationale to target the NRG1-ErbB3-ErbB2 axis as a novel treatment strategy in a subset of cutaneous melanomas

HER3 as biomarker and therapeutic target in pancreatic cancer: new insights in pertuzumab therapy in preclinical models.

International audienceThe anti-HER2 antibody pertuzumab inhibits HER2 dimerization and affects HER2/HER3 dimer formation and signaling. As HER3 and its ligand neuregulin are implicated in pancreatic tumorigenesis, we investigated whether HER3 expression could be a predictive biomarker of pertuzumab efficacy in HER2low-expressing pancreatic cancer. We correlated in vitro and in vivo HER3 expression and neuregulin dependency with the inhibitory effect of pertuzumab on cell viability and tumor progression. HER3 knockdown in BxPC-3 cells led to resistance to pertuzumab therapy. Pertuzumab treatment of HER3-expressing pancreatic cancer cells increased HER3 at the cell membrane, whereas the anti-HER3 monoclonal antibody 9F7-F11 down-regulated it. Both antibodies blocked HER3 and AKT phosphorylation and inhibited HER2/HER3 heterodimerization but affected differently HER2 and HER3 homodimers. The pertuzumab/9F7-F11 combination enhanced tumor inhibition and the median survival time in mice xenografted with HER3-expressing pancreatic cancer cells. Finally, HER2 and HER3 were co-expressed in 11% and HER3 alone in 27% of the 45 pancreatic ductal adenocarcinomas analyzed by immunohistochemistry. HER3 is essential for pertuzumab efficacy in HER2low-expressing pancreatic cancer and HER3 expression might be a predictive biomarker of pertuzumab efficacy in such cancers. Further studies in clinical samples are required to confirm these findings and the interest of combining anti-HER2 and anti-HER3 therapeutic antibodies

Interest of cellular overexpression or induction of Heat Shock proteins in experimental model of articular diseases : Validation of a new electroporation system

Lors des pathologies articulaires, les chondrocytes sont soumis à différents processus qui concourent à la dégradation du cartilage articulaire soit en entraînant la mort par apoptose (nonrenouvellement des constituants de la matrice) soit par l’activation de protéases détruisant les constituants matriciels. Le potentiel chondroprotecteur des protéines de stress (Hsp70 / Hsp27) lors des pathologies dégénératives ayant été démontré, nous avons souhaité évaluer l'intérêt thérapeutique de l’induction de ces protéines par un inhibiteur réversible du protéasome (MG132) dans un modèle expérimental : modèle par section du ligament croisé antérieur (SLCA). Au cours de cette étude, nous avons du évaluer un nouveau système de vectorisation afin de surexprimer les protéines de stress dans le cartilage articulaire. Cette technique (électroporation biphasique) repose sur la dissociation des impulsions perméabilisantes et électrophorétiques. Nous avons donc développé des plasmides nous permettant de surexprimer ces protéines, fusionnées à une protéine traceur, facilitant ainsi leur détection dans le tissu ciblé. Puis, nous avons évalué l’innocuité et l’efficacité des impulsions sur des tissus sains et pathologiques (dégénératifs et inflammatoires). Nous avons constaté que cette technique, en plus de limiter les altérations du tissu articulaire ou les phénomènes de dissémination, offrait des propriétés d’adressage tissulaire de part la multiplicité des combinaisons d’impulsions (nombre, fréquence et intensité). Enfin, les effets de l’induction (MG132) des Hsps sur un modèle physiopathologique (SLCA) ont été évalués et nous avons pu montrer une diminution de la sévérité des atteintes articulaires, tant au niveau du cartilage que de la membrane synoviale. Cette molécule non seulement permet à la fois de renforcer la résistance des chondrocytes aux atteintes mais également de limiter l’amplitude de la réponse inflammatoire qui participe à la dégradation.During articular diseases, chondrocytes suffer different mechanisms which take part in the degradation of the cartilage, either by generating cell death by apoptosis (without renewal of extracellular matrix components), or by protease activation which destroy matrix components. Based on the cytoprotective potential of Heat Shock proteins (Hsp70 and Hsp27) during degenerative diseases, we evaluated the therapeutic interest of these proteins induced by a transient proteasome inhibitor (MG132), in an experimental model, by transection of the anterior cruciate ligament (ACLT). During this study, we have evaluated a new electroporation system to overexpress HSPs in articular cartilage. This technique is based on two sets of electric pulses, wich have two roles, to permeabilize the target and to transport DNA across the permeabilized membrane. We have developed expression vectors to generate a fusion protein (Hsps linked to GFP). Effectively, GFP permit to detect simply the fusion protein in the targeted tissue by fluorescence. Besides, we have evaluated safety and efficiency of electric pulses on healthy and alterated tissues (degenerative and inflammatory). We have reported that this technique could limit articular tissue damages and, moreover, could offer the ability to target more specifically this tissue. Indeed, this apparatus allows a great number of electrics pulses combinations (number, frequency, intensity). Finally, the effects of the induction via MG132 of Hsps in a physiopathological ACLT model, have been evaluated and we have shown a decrease of severity of joint lesions, in cartilage and synovial tissues. This molecule has the advantage to reinforce the resistance of chondrocytes at stressful stimuli and moreover, to limite the amplitude of inflammatory response which contribute to the magnification of extracellular matrix destruction

Intérêt de la vectorisation et/ou de l'induction des protéines de stress dans les modèles expérimentaux de pathologies ostéoarticulaires : Validation de l'électroporation biphasique

During articular diseases, chondrocytes suffer different mechanisms which take part in the degradation of the cartilage, either by generating cell death by apoptosis (without renewal of extracellular matrix components), or by protease activation which destroy matrix components. Based on the cytoprotective potential of Heat Shock proteins (Hsp70 and Hsp27) during degenerative diseases, we evaluated the therapeutic interest of these proteins induced by a transient proteasome inhibitor (MG132), in an experimental model, by transection of the anterior cruciate ligament (ACLT). During this study, we have evaluated a new electroporation system to overexpress HSPs in articular cartilage. This technique is based on two sets of electric pulses, wich have two roles, to permeabilize the target and to transport DNA across the permeabilized membrane. We have developed expression vectors to generate a fusion protein (Hsps linked to GFP). Effectively, GFP permit to detect simply the fusion protein in the targeted tissue by fluorescence. Besides, we have evaluated safety and efficiency of electric pulses on healthy and alterated tissues (degenerative and inflammatory). We have reported that this technique could limit articular tissue damages and, moreover, could offer the ability to target more specifically this tissue. Indeed, this apparatus allows a great number of electrics pulses combinations (number, frequency, intensity). Finally, the effects of the induction via MG132 of Hsps in a physiopathological ACLT model, have been evaluated and we have shown a decrease of severity of joint lesions, in cartilage and synovial tissues. This molecule has the advantage to reinforce the resistance of chondrocytes at stressful stimuli and moreover, to limite the amplitude of inflammatory response which contribute to the magnification of extracellular matrix destruction.Lors des pathologies articulaires, les chondrocytes sont soumis à différents processus qui concourent à la dégradation du cartilage articulaire soit en entraînant la mort par apoptose (nonrenouvellement des constituants de la matrice) soit par l?activation de protéases détruisant les constituants matriciels. Le potentiel chondroprotecteur des protéines de stress (Hsp70 / Hsp27) lors des pathologies dégénératives ayant été démontré, nous avons souhaité évaluer l'intérêt thérapeutique de l'induction de ces protéines par un inhibiteur réversible du protéasome (MG132) dans un modèle expérimental : modèle par section du ligament croisé antérieur (SLCA). Au cours de cette étude, nous avons du évaluer un nouveau système de vectorisation afin de surexprimer les protéines de stress dans le cartilage articulaire. Cette technique (électroporation biphasique) repose sur la dissociation des impulsions perméabilisantes et électrophorétiques. Nous avons donc développé des plasmides nous permettant de surexprimer ces protéines, fusionnées à une protéine traceur, facilitant ainsi leur détection dans le tissu ciblé. Puis, nous avons évalué l'innocuité et l'efficacité des impulsions sur des tissus sains et pathologiques (dégénératifs et inflammatoires). Nous avons constaté que cette technique, en plus de limiter les altérations du tissu articulaire ou les phénomènes de dissémination, offrait des propriétés d'adressage tissulaire de part la multiplicité des combinaisons d'impulsions (nombre, fréquence et intensité). Enfin, les effets de l'induction (MG132) des Hsps sur un modèle physiopathologique (SLCA) ont été évalués et nous avons pu montrer une diminution de la sévérité des atteintes articulaires, tant au niveau du cartilage que de la membrane synoviale. Cette molécule non seulement permet à la fois de renforcer la résistance des chondrocytes aux atteintes mais également de limiter l'amplitude de la réponse inflammatoire qui participe à la dégradation

Intérêt de la vectorisation et/ou de l'induction des protéines de stress dans les modèles expérimentaux de pathologies ostéoarticulaires (Validation de l'électroporation biphasique)

Lors des pathologies articulaires, les chondrocytes sont soumis à différents processus qui concourent à la dégradation du cartilage articulaire soit en entraînant la mort par apoptose (nonrenouvellement des constituants de la matrice) soit par l activation de protéases détruisant les constituants matriciels. Le potentiel chondroprotecteur des protéines de stress (Hsp70 / Hsp27) lors des pathologies dégénératives ayant été démontré, nous avons souhaité évaluer l'intérêt thérapeutique de l induction de ces protéines par un inhibiteur réversible du protéasome (MG132) dans un modèle expérimental : modèle par section du ligament croisé antérieur (SLCA). Au cours de cette étude, nous avons du évaluer un nouveau système de vectorisation afin de surexprimer les protéines de stress dans le cartilage articulaire. Cette technique (électroporation biphasique) repose sur la dissociation des impulsions perméabilisantes et électrophorétiques. Nous avons donc développé des plasmides nous permettant de surexprimer ces protéines, fusionnées à une protéine traceur, facilitant ainsi leur détection dans le tissu ciblé. Puis, nous avons évalué l innocuité et l efficacité des impulsions sur des tissus sains et pathologiques (dégénératifs et inflammatoires). Nous avons constaté que cette technique, en plus de limiter les altérations du tissu articulaire ou les phénomènes de dissémination, offrait des propriétés d adressage tissulaire de part la multiplicité des combinaisons d impulsions (nombre, fréquence et intensité). Enfin, les effets de l induction (MG132) des Hsps sur un modèle physiopathologique (SLCA) ont été évalués et nous avons pu montrer une diminution de la sévérité des atteintes articulaires, tant au niveau du cartilage que de la membrane synoviale. Cette molécule non seulement permet à la fois de renforcer la résistance des chondrocytes aux atteintes mais également de limiter l amplitude de la réponse inflammatoire qui participe à la dégradation.During articular diseases, chondrocytes suffer different mechanisms which take part in the degradation of the cartilage, either by generating cell death by apoptosis (without renewal of extracellular matrix components), or by protease activation which destroy matrix components. Based on the cytoprotective potential of Heat Shock proteins (Hsp70 and Hsp27) during degenerative diseases, we evaluated the therapeutic interest of these proteins induced by a transient proteasome inhibitor (MG132), in an experimental model, by transection of the anterior cruciate ligament (ACLT). During this study, we have evaluated a new electroporation system to overexpress HSPs in articular cartilage. This technique is based on two sets of electric pulses, wich have two roles, to permeabilize the target and to transport DNA across the permeabilized membrane. We have developed expression vectors to generate a fusion protein (Hsps linked to GFP). Effectively, GFP permit to detect simply the fusion protein in the targeted tissue by fluorescence. Besides, we have evaluated safety and efficiency of electric pulses on healthy and alterated tissues (degenerative and inflammatory). We have reported that this technique could limit articular tissue damages and, moreover, could offer the ability to target more specifically this tissue. Indeed, this apparatus allows a great number of electrics pulses combinations (number, frequency, intensity). Finally, the effects of the induction via MG132 of Hsps in a physiopathological ACLT model, have been evaluated and we have shown a decrease of severity of joint lesions, in cartilage and synovial tissues. This molecule has the advantage to reinforce the resistance of chondrocytes at stressful stimuli and moreover, to limite the amplitude of inflammatory response which contribute to the magnification of extracellular matrix destruction.NANCY1-Bib. numérique (543959902) / SudocSudocFranceF

Le récepteur HER3 ou ERBB3 : La face cachée de la planète ERBB

International audienc

Unbiased Electro-Optic Waveguide as a Sensitive Nuclear Magnetic Resonance Sensor

International audience— A pigtailed Ti:LiNbO 3 waveguide is here associated to a specific nuclear magnetic resonant coil to perform a low invasive magnetic field measurement. The developed device exploits a passive electro-optic transduction between the measured magnetic field and polarization state modulation of a laser probe beam. Because of the use of integrated optics, the coil electromotive force induces a dramatically enhanced electric field, thus leading to sensitivity improvement. A minimum detectable magnetic field lower than 60 fT · Hz −1/2 is achieved at the resonant frequency of 128 MHz. A dynamic range exceeding 100 dB is experimentally demonstrated

Lithium niobate polarization-state-modulator for electromagnetic sensing

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Name="Table Classic 3"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Classic 4"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Colorful 1"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Colorful 2"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Colorful 3"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Columns 1"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Columns 2"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Columns 3"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Columns 4"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Columns 5"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Grid 1"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Grid 2"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Grid 3"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Grid 4"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Grid 5"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Grid 6"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Grid 7"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Grid 8"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table List 1"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table List 2"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table List 3"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table List 4"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table List 5"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table List 6"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table List 7"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table List 8"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table 3D effects 1"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table 3D effects 2"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table 3D effects 3"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Contemporary"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Elegant"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Professional"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Subtle 1"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Subtle 2"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Web 1"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Web 2"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Web 3"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Balloon Text"/&gt <w:LsdException Locked="false" Priority="39" Name="Table Grid"/&gt <w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true" Name="Table Theme"/&gt <w:LsdException Locked="false" SemiHidden="true" Name="Placeholder Text"/&gt <w:LsdException Locked="false" Priority="1" QFormat="true" Name="No Spacing"/&gt <w:LsdException Locked="false" Priority="60" Name="Light Shading"/&gt <w:LsdException Locked="false" Priority="61" Name="Light List"/&gt <w:LsdException Locked="false" Priority="62" Name="Light Grid"/&gt <w:LsdException Locked="false" Priority="63" Name="Medium Shading 1"/&gt <w:LsdException Locked="false" Priority="64" Name="Medium Shading 2"/&gt <w:LsdException Locked="false" Priority="65" Name="Medium List 1"/&gt <w:LsdException Locked="false" Priority="66" Name="Medium List 2"/&gt <w:LsdException Locked="false" Priority="67" Name="Medium Grid 1"/&gt <w:LsdException Locked="false" Priority="68" Name="Medium Grid 2"/&gt <w:LsdException Locked="false" Priority="69" Name="Medium Grid 3"/&gt <w:LsdException Locked="false" Priority="70" Name="Dark List"/&gt <w:LsdException Locked="false" Priority="71" Name="Colorful Shading"/&gt <w:LsdException Locked="false" Priority="72" Name="Colorful List"/&gt <w:LsdException Locked="false" Priority="73" Name="Colorful Grid"/&gt <w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 1"/&gt <w:LsdException Locked="false" Priority="61" Name="Light List Accent 1"/&gt <w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 1"/&gt <w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 1"/&gt <w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 1"/&gt <w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 1"/&gt <w:LsdException Locked="false" SemiHidden="true" Name="Revision"/&gt <w:LsdException Locked="false" Priority="34" QFormat="true" Name="List Paragraph"/&gt <w:LsdException Locked="false" Priority="29" QFormat="true" Name="Quote"/&gt <w:LsdException Locked="false" Priority="30" QFormat="true" Name="Intense Quote"/&gt <w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 1"/&gt <w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 1"/&gt <w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 1"/&gt <w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 1"/&gt <w:LsdException Locked="false" Priority="70" Name="Dark List Accent 1"/&gt <w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 1"/&gt <w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 1"/&gt <w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 1"/&gt <w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 2"/&gt <w:LsdException Locked="false" Priority="61" Name="Light List Accent 2"/&gt <w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 2"/&gt <w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 2"/&gt <w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 2"/&gt <w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 2"/&gt <w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 2"/&gt <w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 2"/&gt <w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 2"/&gt <w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 2"/&gt <w:LsdException Locked="false" Priority="70" Name="Dark List Accent 2"/&gt <w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 2"/&gt <w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 2"/&gt <w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 2"/&gt <w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 3"/&gt <w:LsdException Locked="false" Priority="61" Name="Light List Accent 3"/&gt <w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 3"/&gt <w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 3"/&gt <w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 3"/&gt <w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 3"/&gt <w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 3"/&gt <w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 3"/&gt <w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 3"/&gt <w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 3"/&gt <w:LsdException Locked="false" Priority="70" Name="Dark List Accent 3"/&gt <w:LsdException Locked="false" Priority="71" Name="Colorful Shading A