Modulation of PKM alternative splicing by PTBP1 promotes gemcitabine resistance in pancreatic cancer cells

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and incurable disease. Poor prognosis is due to multiple reasons, including acquisition of resistance to gemcitabine, the first-line chemotherapeutic approach. Thus, there is a strong need for novel therapies, targeting more directly the molecular aberrations of this disease. We found that chronic exposure of PDAC cells to gemcitabine selected a subpopulation of cells that are drug-resistant (DR-PDAC cells). Importantly, alternative splicing (AS) of the pyruvate kinase gene (PKM) was differentially modulated in DR-PDAC cells, resulting in promotion of the cancer-related PKM2 isoform, whose high expression also correlated with shorter recurrence-free survival in PDAC patients. Switching PKM splicing by antisense oligonucleotides to favor the alternative PKM1 variant rescued sensitivity of DR-PDAC cells to gemcitabine and cisplatin, suggesting that PKM2 expression is required to withstand drug-induced genotoxic stress. Mechanistically, upregulation of the polypyrimidine-tract binding protein (PTBP1), a key modulator of PKM splicing, correlated with PKM2 expression in DR-PDAC cell lines. PTBP1 was recruited more efficiently to PKM pre-mRNA in DR- than in parental PDAC cells. Accordingly, knockdown of PTBP1 in DR-PDAC cells reduced its recruitment to the PKM pre-mRNA, promoted splicing of the PKM1 variant and abolished drug resistance. Thus, chronic exposure to gemcitabine leads to upregulation of PTBP1 and modulation of PKM AS in PDAC cells, conferring resistance to the drug. These findings point to PKM2 and PTBP1 as new potential therapeutic targets to improve response of PDAC to chemotherapy.Oncogene advance online publication, 3 August 2015; doi:10.1038/onc.2015.270

Melting and Dimensionality of the Vortex Lattice in Underdoped YBa2Cu3O6.60

Muon spin rotation measurements of the magnetic field distribution in the vortex state of the oxygen deficient high-Tc superconductor YBa{2}Cu{3}O{6.60} reveal a vortex-lattice melting transition at much lower temperature than that in the fully oxygenated material. The transition is best described by a model in which adjacent layers of ``pancake'' vortices decouple in the liquid phase. Evidence is also found for a pinning-induced crossover from a solid 3D to quasi-2D vortex lattice, similar to that observed in the highly anisotropic superconductor Bi{2+x}Sr{2-x}CaCu{2}O{8+y}.Comment: 8 pages, 4 figures, 5 postscript file

Longitudinal Current Dissipation in Bose-glass Superconductors

A scaling theory of vortex motion in Bose glass superconductors with currents parallel to the common direction of the magnetic field and columnar defects is presented. Above the Bose-glass transition the longitudinal DC resistivity $\rho_{||}(T)\sim (T-T_{BG})^{\nu' z'}$ vanishes much faster than the corresponding transverse resistivity $\rho_{\perp}(T)\sim (T-T_{BG})^{\nu' (z'-2)}$, thus {\it reversing} the usual anisotropy of electrical transport in the normal state of layered superconductors. In the presence of a current $\bf J$ at an angle $\theta_J$ with the common field and columnar defect axis, the electric field angle $\theta_E$ approaches $\pi/2$ as $T\rightarrow T_{BG}^+$. Scaling also predicts the behavior of penetration depths for the AC currents as $T\rightarrow T_{BG}^-$, and implies a {\it jump discontinuity} at $T_{BG}$ in the superfluid density describing transport parallel to the columns.Comment: 5 pages, revte

Effect of disorder on the vortex-lattice melting transition

We use a three dimensional stacked triangular network of Josephson junctions as a model for the study of vortex structure in the mixed state of high Tc superconductors. We show that the addition of disorder destroys the first order melting transition occurring for clean samples. The melting transition splits in two different (continuous) transitions, ocurring at temperatures Ti and Tp (>Ti). At Ti the perpendicular-to-field superconductivity is lost, and at Tp the parallel-to-field superconductivity is lost. These results agree well with recent experiments in YBaCuO.Comment: 4 pages + 2 figure

Critical Fluctuations and Disorder at the Vortex Liquid to Crystal Transition in Type-II Superconductors

We present a functional renormalization group (FRG) analysis of a Landau-Ginzburg model of type-II superconductors (generalized to $n/2$ complex fields) in a magnetic field, both for a pure system, and in the presence of quenched random impurities. Our analysis is based on a previous FRG treatment of the pure case [E.Br\'ezin et. al., Phys. Rev. B, {\bf 31}, 7124 (1985)] which is an expansion in $\epsilon = 6-d$. If the coupling functions are restricted to the space of functions with non-zero support only at reciprocal lattice vectors corresponding to the Abrikosov lattice, we find a stable FRG fixed point in the presence of disorder for $1<n<4$, identical to that of the disordered $O(n)$ model in $d-2$ dimensions. The pure system has a stable fixed point only for $n>4$ and so the physical case ($n = 2$) is likely to have a first order transition. We speculate that the recent experimental findings that disorder removes the apparent first order transition are consistent with these calculations.Comment: 4 pages, no figures, typeset using revtex (v3.0

Direct observation of the washboard noise of a driven vortex lattice in a high-temperature superconductor, Bi2Sr2CaCu2Oy

We studied the conduction noise spectrum in the vortex state of a high-temperature superconductor, Bi2Sr2CaCu2Oy, subject to a uniform driving force. Two characteristic features, a broadband noise (BBN) and a narrow-band noise (NBN), were observed in the vortex-solid phase. The origin of the large BBN was determined to be plastic motion of the vortices, whereas the NBN was found to originate from the washboard modulation of the translational velocity of the driven vortices. We believe this to be the first observation ofComment: 4 pages, 4 figures, to appear in Phys. Rev. Let

Topological Defects in the Random-Field XY Model and the Pinned Vortex Lattice to Vortex Glass Transition in Type-II Superconductors

As a simplified model of randomly pinned vortex lattices or charge-density waves, we study the random-field XY model on square ($d=2$) and simple cubic ($d=3$) lattices. We verify in Monte Carlo simulations, that the average spacing between topological defects (vortices) diverges more strongly than the Imry-Ma pinning length as the random field strength, $H$, is reduced. We suggest that for $d=3$ the simulation data are consistent with a topological phase transition at a nonzero critical field, $H_c$, to a pinned phase that is defect-free at large length-scales. We also discuss the connection between the possible existence of this phase transition in the random-field XY model and the magnetic field driven transition from pinned vortex lattice to vortex glass in weakly disordered type-II superconductors.Comment: LATEX file; 5 Postscript figures are available from [email protected]

The phase diagram of high-Tc's: Influence of anisotropy and disorder

We propose a phase diagram for the vortex structure of high temperature superconductors which incorporates the effects of anisotropy and disorder. It is based on numerical simulations using the three-dimensional Josephson junction array model. We support the results with an estimation of the internal energy and configurational entropy of the system. Our results give a unified picture of the behavior of the vortex lattice, covering from the very anysotropic BiSrCaCuO to the less anisotropic YBaCuO, and from the first order melting ocurring in clean samples to the continuous transitions observed in samples with defects.Comment: 8 pages with 7 figure

Plasticity and memory effects in the vortex solid phase of twinned YBa2Cu3O7 single crystals

We report on marked memory effects in the vortex system of twinned YBa2Cu3O7 single crystals observed in ac susceptibility measurements. We show that the vortex system can be trapped in different metastable states with variable degree of order arising in response to different system histories. The pressure exerted by the oscillating ac field assists the vortex system in ordering, locally reducing the critical current density in the penetrated outer zone of the sample. The robustness of the ordered and disordered states together with the spatial profile of the critical current density lead to the observed memory effects

Is there a Phase Transition to the Flux Lattice State?

The sharp drops in the resistance and magnetization which are usually attributed to a phase transition from the vortex liquid state to a crystal state are explained instead as a crossover between three and two dimensional behavior, which occurs when the phase coherence length in the liquid becomes comparable to the sample thickness. Estimates of the width of the crossover region and the phase coherence length scales are in agreement with experiment.Comment: 4 pages, RevTe