A novel mechanism of action of HER2 targeted immunotherapy is explained by inhibition of NRF2 function in ovarian cancer cells

Nuclear erythroid related factor-2 (NRF2) is known to promote cancer therapeutic detoxification and crosstalk with growth promoting pathways. HER2 receptor tyrosine kinase is frequently overexpressed in cancers leading to uncontrolled receptor activation and signaling. A combination of HER2 targeting monoclonal antibodies shows greater anticancer efficacy than the single targeting antibodies, however, its mechanism of action is largely unclear. Here we report novel actions of anti-HER2 drugs, Trastuzumab and Pertuzumab, involving NRF2. HER2 targeting by antibodies inhibited growth in association with persistent generation of reactive oxygen species (ROS), glutathione (GSH) depletion, reduction in NRF2 levels and inhibition of NRF2 function in ovarian cancer cell lines. The combination of antibodies produced more potent effects than single alone; downregulated NRF2 substrates by repressing the Antioxidant Response (AR) pathway with concomitant transcriptional inhibition of NRF2. We showed the antibody combination produced increased methylation at the NRF2 promoter consistent with repression of NRF2 antioxidant function, as HDAC and methylation inhibitors reversed such produced transcriptional effects. These findings demonstrate a novel mechanism and role for NRF2 in mediating the response of cancer cells to the combination of Trastuzumab and Pertuzumab and reinforce the importance of NRF2 in drug resistance and as a key anticancer target

GINZBURG-LANDAU THEORY OF VORTICES IN dd-WAVE SUPERCONDUCTORS

Ginzburg-Landau theory is used to study the properties of single vortices and of the Abrikosov vortex lattice in a $d_{x^2-y^2}$ superconductor. For a single vortex, the $s$-wave order parameter has the expected four-lobe structure in a ring around the core and falls off like $1/r^2$ at large distances. The topological structure of the $s$-wave order parameter consists of one counter-rotating unit vortex, centered at the core, surrounded by four symmetrically placed positive unit vortices. The Abrikosov lattice is shown to have a triangular structure close to $T_c$ and an oblique structure at lower temperatures. Comparison is made to recent neutron scattering data.Comment: 4 pages, REVTeX, 3 figures available upon reques

Systems analysis of drug-induced receptor tyrosine kinase reprogramming following targeted mono- and combination anti-cancer therapy

The receptor tyrosine kinases (RTKs) are key drivers of cancer progression and targets for drug therapy. A major challenge in anti-RTK treatment is the dependence of drug effectiveness on co-expression of multiple RTKs which defines resistance to single drug therapy. Reprogramming of the RTK network leading to alteration in RTK co-expression in response to drug intervention is a dynamic mechanism of acquired resistance to single drug therapy in many cancers. One route to overcome this resistance is combination therapy. We describe the results of a joint in silico, in vitro, and in vivo investigations on the efficacy of trastuzumab, pertuzumab and their combination to target the HER2 receptors. Computational modelling revealed that these two drugs alone and in combination differentially suppressed RTK network activation depending on RTK co-expression. Analyses of mRNA expression in SKOV3 ovarian tumour xenograft showed up-regulation of HER3 following treatment. Considering this in a computational model revealed that HER3 up-regulation reprograms RTK kinetics from HER2 homodimerisation to HER3/HER2 heterodimerisation. The results showed synergy of the trastuzumab and pertuzumab combination treatment of the HER2 overexpressing tumour can be due to an independence of the combination effect on HER3/HER2 composition when it changes due to drug-induced RTK reprogramming

Clapping modes in unconventional superconductors

We consider a superconducting state with a mixed symmetry order parameter components, e.g. $d+is$ or $d+id'$ with $d'= d_{xy}$. We argue for the existence of the new orbital magnetization mode which corresponds to the oscillations of relative phase $\phi$ between two components around an equilibrium value of $\phi = \frac{\pi}{2}$. It is similar to the so called ``clapping'' mode in superfluid $^3He-A$. We estimate the frequency of this mode $\omega_0(B,T)$ depending on the field and temperature for the specific case of magnetic field induced $d'$ state. We find that this mode is {\em tunable} with an applied magnetic field with \omega_0(B,T) \propto B \0, where \0 is the magnitude of the d-wave order parameter. We argue also that similar filed induced clapping mode should be present in an organic p-wave superconductors.Comment: M2S-HTSC-VI Proceedings, Feb 2000, Houston, TX, USA; 4 pages. Physica C, to be publishe

NMR relaxation time around a vortex in stripe superconductors

Site-dependent NMR relaxation time $T_1({\bf r})$ is calculated in the vortex state using the Bogoliubov-de Gennes theory, taking account of possible "field-induced stripe'' states in which the magnetism arises locally around a vortex core in d-wave superconductivity. The recently observed huge enhancement $T_1^{-1}({\bf r})$ below $T_c$ at a core site in Tl$_2$Ba$_2$CuO$_6$ is explained. The field-induced stripe picture explains consistently other relevant STM and neutron experiments.Comment: 4 pages, 4 figure

The Effects of Phase Separation in the Cuprate Superconductors

Phase separation has been observed by several different experiments and it is believed to be closely related with the physics of cuprates but its exactly role is not yet well known. We propose that the onset of pseudogap phenomenon or the upper pseudogap temperature $T^*$ has its origin in a spontaneous phase separation transition at the temperature $T_{ps}=T^*$. In order to perform quantitative calculations, we use a Cahn-Hilliard (CH) differential equation originally proposed to the studies of alloys and on a spinodal decomposition mechanism. Solving numerically the CH equation it is possible to follow the time evolution of a coarse-grained order parameter which satisfies a Ginzburg-Landau free-energy functional commonly used to model superconductors. In this approach, we follow the process of charge segregation into two main equilibrium hole density branches and the energy gap normally attributed to the upper pseudogap arises as the free-energy potential barrier between these two equilibrium densities below $T_{ps}$. This simulation provides quantitative results %on the hole doping and temperature %dependence of the degree of the charge inhomogeneity in agreement with %some experiments and the simulations reproduce the observed stripe and granular pattern of segregation. Furthermore, with a Bogoliubov-deGennes (BdG) local superconducting critical temperature calculation for the lower pseudogap or the onset of local superconductivity, it yields novel interpretation of several non-conventional measurements on cuprates.Comment: Published versio

ss- and dxyd_{xy}-wave components induced around a vortex in dx2−y2d_{x^2-y^2}-wave superconductors

Vortex structure of $d_{x^2-y^2}$-wave superconductors is microscopically analyzed in the framework of the quasi-classical Eilenberger equations. If the pairing interaction contains an $s$-wave ($d_{xy}$-wave) component in addition to a $d_{x^2-y^2}$-wave component, the $s$-wave ($d_{xy}$-wave) component of the order parameter is necessarily induced around a vortex in $d_{x^2-y^2}$-wave superconductors. The spatial distribution of the induced $s$-wave and $d_{xy}$-wave components is calculated. The $s$-wave component has opposite winding number around vortex near the $d_{x^2-y^2}$-vortex core and its amplitude has the shape of a four-lobe clover. The amplitude of $d_{xy}$-component has the shape of an octofoil. These are consistent with results based on the GL theory.Comment: RevTex,9 pages, 6 figures in a uuencoded fil