The Amplitude of Non-Equilibrium Quantum Interference in Metallic Mesoscopic Systems

We study the influence of a DC bias voltage V on quantum interference corrections to the measured differential conductance in metallic mesoscopic wires and rings. The amplitude of both universal conductance fluctuations (UCF) and Aharonov-Bohm effect (ABE) is enhanced several times for voltages larger than the Thouless energy. The enhancement persists even in the presence of inelastic electron-electron scattering up to V ~ 1 mV. For larger voltages electron-phonon collisions lead to the amplitude decaying as a power law for the UCF and exponentially for the ABE. We obtain good agreement of the experimental data with a model which takes into account the decrease of the electron phase-coherence length due to electron-electron and electron-phonon scattering.Comment: New title, refined analysis. 7 pages, 3 figures, to be published in Europhysics Letter

Doubly connected minimal surfaces and extremal harmonic mappings

The concept of a conformal deformation has two natural extensions: quasiconformal and harmonic mappings. Both classes do not preserve the conformal type of the domain, however they cannot change it in an arbitrary way. Doubly connected domains are where one first observes nontrivial conformal invariants. Herbert Groetzsch and Johannes C. C. Nitsche addressed this issue for quasiconformal and harmonic mappings, respectively. Combining these concepts we obtain sharp estimates for quasiconformal harmonic mappings between doubly connected domains. We then apply our results to the Cauchy problem for minimal surfaces, also known as the Bjorling problem. Specifically, we obtain a sharp estimate of the modulus of a doubly connected minimal surface that evolves from its inner boundary with a given initial slope.Comment: 35 pages, 2 figures. Minor edits, references adde

Mappings of least Dirichlet energy and their Hopf differentials

The paper is concerned with mappings between planar domains having least Dirichlet energy. The existence and uniqueness (up to a conformal change of variables in the domain) of the energy-minimal mappings is established within the class $\bar{\mathscr H}_2(X, Y)$ of strong limits of homeomorphisms in the Sobolev space $W^{1,2}(X, Y)$, a result of considerable interest in the mathematical models of Nonlinear Elasticity. The inner variation leads to the Hopf differential $h_z \bar{h_{\bar{z}}} dz \otimes dz$ and its trajectories. For a pair of doubly connected domains, in which $X$ has finite conformal modulus, we establish the following principle: A mapping $h \in \bar{\mathscr H}_2(X, Y)$ is energy-minimal if and only if its Hopf-differential is analytic in $X$ and real along the boundary of $X$. In general, the energy-minimal mappings may not be injective, in which case one observes the occurrence of cracks in $X$. Nevertheless, cracks are triggered only by the points in the boundary of $Y$ where $Y$ fails to be convex. The general law of formation of cracks reads as follows: Cracks propagate along vertical trajectories of the Hopf differential from the boundary of $X$ toward the interior of $X$ where they eventually terminate before making a crosscut.Comment: 51 pages, 4 figure

On Non-Abelian Symplectic Cutting

We discuss symplectic cutting for Hamiltonian actions of non-Abelian compact groups. By using a degeneration based on the Vinberg monoid we give, in good cases, a global quotient description of a surgery construction introduced by Woodward and Meinrenken, and show it can be interpreted in algebro-geometric terms. A key ingredient is the `universal cut' of the cotangent bundle of the group itself, which is identified with a moduli space of framed bundles on chains of projective lines recently introduced by the authors.Comment: Various edits made, to appear in Transformation Groups. 28 pages, 8 figure

Effects of Long-term Exposure on E-glass Composite Material Subjected to Stress Corrosion in a Saline Medium

[EN] This work provides an insight on very long-term degradation of polyester-fiber glass composites immersed more than 30,000 h in saline medium under service stresses. Samples were loaded under bending conditions with stresses both in the elastic and plastic fields, with the result that characteristics in a flexural mode were able to be determined and the ensuing decrease in characteristics was fitted to an exponential model. The degree of losses ranged from 25 to 31% for the bending modulus, from 28 to 35% for the flexural strength, and from 40 to 51% for the specific fracture energy. The most notable losses were for specimens immersed in artificial sea water under a continuous stress of 140 MPa, corresponding to the plastic behavior of the material. Although the existence of matrix plasticization is doubtful, the osmotic effects of the diffusion on the matrix and the junction to the fibers, the presence of microcracks, and the effects of chemical ions in the medium on the surface fiber composition became evident in the strength degradation of the material.Segovia López, EF.; Salvador Moya, MD.; Sahuquillo Navarro, O.; Vicente Escuder, Á. (2007). Effects of Long-term Exposure on E-glass Composite Material Subjected to Stress Corrosion in a Saline Medium. Journal of Composite Materials. 41(17):2119-2128. doi:10.1177/0021998307074134S21192128411

PANTHER: AZD8931, inhibitor of EGFR, ERBB2 and ERBB3 signalling, combined with FOLFIRI: a Phase I/II study to determine the importance of schedule and activity in colorectal cancer

BACKGROUND: Epidermal growth factor receptor (EGFR) is a therapeutic target to which HER2/HER3 activation may contribute resistance. This Phase I/II study examined the toxicity and efficacy of high-dose pulsed AZD8931, an EGFR/HER2/HER3 inhibitor, combined with chemotherapy, in metastatic colorectal cancer (CRC). METHODS: Treatment-naive patients received 4-day pulses of AZD8931 with irinotecan/5-FU (FOLFIRI) in a Phase I/II single-arm trial. Primary endpoint for Phase I was dose limiting toxicity (DLT); for Phase II best overall response. Samples were analysed for pharmacokinetics, EGFR dimers in circulating exosomes and Comet assay quantitating DNA damage. RESULTS: Eighteen patients received FOLFIRI and AZD8931. At 160 mg bd, 1 patient experienced G3 DLT; 160 mg bd was used for cohort expansion. No grade 5 adverse events (AE) reported. Seven (39%) and 1 (6%) patients experienced grade 3 and grade 4 AEs, respectively. Of 12 patients receiving 160 mg bd, best overall response rate was 25%, median PFS and OS were 8.7 and 21.2 months, respectively. A reduction in circulating HER2/3 dimer in the two responding patients after 12 weeks treatment was observed. CONCLUSIONS: The combination of pulsed high-dose AZD8931 with FOLFIRI has acceptable toxicity. Further studies of TKI sequencing may establish a role for pulsed use of such agents rather than continuous exposure. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number: NCT01862003

Detecting intratumoral heterogeneity of EGFR activity by liposome-based in vivo transfection of a fluorescent biosensor

Despite decades of research in the epidermal growth factor receptor (EGFR) signalling field, and many targeted anti-cancer drugs that have been tested clinically, the success rate for these agents in the clinic is low, particularly in terms of the improvement of overall survival. Intratumoral heterogeneity is proposed as a major mechanism underlying treatment failure of these molecule-targeted agents. Here we highlight the application of fluorescence lifetime microscopy (FLIM)-based biosensing to demonstrate intratumoral heterogeneity of EGFR activity. For sensing EGFR activity in cells, we used a genetically encoded CrkII-based biosensor which undergoes conformational changes upon tyrosine-221 phosphorylation by EGFR. We transfected this biosensor into EGFR-positive tumour cells using targeted lipopolyplexes bearing EGFR-binding peptides at their surfaces. In a murine model of basal-like breast cancer, we demonstrated a significant degree of intratumoral heterogeneity in EGFR activity, as well as the pharmacodynamic effect of a radionuclide-labeled EGFR inhibitor in situ. Furthermore, a significant correlation between high EGFR activity in tumour cells and macrophage-tumour cell proximity was found to in part account for the intratumoral heterogeneity in EGFR activity observed. The same effect of macrophage infiltrate on EGFR activation was also seen in a colorectal cancer xenograft. In contrast, a non-small cell lung cancer xenograft expressing a constitutively active EGFR conformational mutant exhibited macrophage proximity-independent EGFR activity. Our study validates the use of this methodology to monitor therapeutic response in terms of EGFR activity. In addition, we found iNOS gene induction in macrophages that are cultured in tumour cell-conditioned media as well as an iNOS activity-dependent increase in EGFR activity in tumour cells. These findings point towards an immune microenvironment-mediated regulation that gives rise to the observed intratumoral heterogeneity of EGFR signalling activity in tumour cells in vivo

HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers

Amplification and oncogenic mutations of ERBB2, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody-drug conjugates (ADCs) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with ERBB2/HER2-amplified or mutant lung cancers. We show that co-treatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy