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

Hall Anomaly and Vortex-Lattice Melting in Superconducting Single Crystal YBa2Cu3O7-d

Sub-nanovolt resolution longitudinal and Hall voltages are measured in an ultra pure YBa2Cu3O7-d single crystal. The Hall anomaly and the first-order vortex-lattice melting transition are observed simultaneously. Changes in the dynamic behavior of the vortex solid and liquid are correlated with features of the Hall conductivity sxy. With the magnetic field oriented at an angle from the twin-boundaries, the Hall conductivity sharply decreases toward large negative values at the vortex-lattice melting transition.Comment: 6 pages, 2 figures included, Postscript, to appear in Phys. Rev. Let

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

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

Disorder and thermally driven vortex-lattice melting in La{2-x}Sr{x}CuO{4} crystals

Magnetization measurements in La{2-x}Sr{x}CuO{4} crystals indicate vortex order-disorder transition manifested by a sharp kink in the second magnetization peak. The transition field exhibits unique temperature dependence, namely a strong decrease with temperature in the entire measured range. This behavior rules out the conventional interpretation of a disorder-driven transition into an entangled vortex solid phase. It is shown that the transition in La{2-x}Sr{x}CuO{4} is driven by both thermally- and disorder-induced fluctuations, resulting in a pinned liquid state. We conclude that vortex solid-liquid, solid-solid and solid to pinned-liquid transitions are different manifestations of the same thermodynamic order-disorder transition, distinguished by the relative contributions of thermal and disorder-induced fluctuations.Comment: To be published in phys. Rev. B Rapid Com

Vortex Lattice Melting into Disentangled Liquid Followed by the 3D-2D Decoupling Transition in YBa_2Cu_4O_8 Single Crystals

A sharp resistance drop associated with vortex lattice melting was observed in high quality YBa_2Cu_4O_8 single crystals. The melting line is well described well by the anisotropic GL theory. Two thermally activated flux flow regions, which were separated by a crossover line B_cr=1406.5(1-T/T_c)/T (T_c=79.0 K, B_cr in T), were observed in the vortex liquid phase. Activation energy for each region was obtained and the corresponding dissipation mechanism was discussed. Our results suggest that the vortex lattice in YBa_2Cu_4O_8 single crystal melts into disentangled liquid, which then undergoes a 3D-2D decoupling transition.Comment: 5 pages, 4 eps figures, RevTex (Latex2.09

Peak effect, vortex-lattice melting-line and order - disorder transition in conventional and high-T superconductors

We investigate the order - disorder transition line from a Bragg glass to an amorphous vortex glass in the H-T phase diagram of three-dimensional type-II superconductors with account of both pinning-caused and thermal fluctuations of the vortex lattice. Our approach is based on the Lindemann criterion and on results of the collective pinning theory and generalizes previous work of other authors. It is shown that the shapes of the order - disorder transition line and the vortex lattice melting curve are determined only by the Ginzburg number, which characterizes thermal fluctuations, and by a parameter which describes the strength of the quenched disorder in the flux-line lattice. In the framework of this unified approach we obtain the H-T phase diagrams for both conventional and high-Tc superconductors. Several well-known experimental results concerning the fishtail effect and the phase diagram of high-Tc superconductors are naturally explained by assuming that a peak effect in the critical current density versus H signalizes the order - disorder transition line in superconductors with point defects.Comment: 15 pages including 11 figure

The interaction of vortices with twin boundaries

Twin boundaries provide a convenient defect for investigating vortex dynamics in superconductors. They occur naturally in YBa{sub 2}Cu{sub 3}O{sub 7}, with well defined planar geometries. They are a strong pinning defect, and at the temperature of the melting transition they are the dominant pinning sites in clean crystals. Twin boundaries are easily seen in polarized light, making their location and number directly observable without special equipment. Finally, they present a highly anisotropic pinning potential to the vortices, creating the possibility of interesting new behavior. In this paper, we describe experiments using twin boundaries to probe two effects in vortex dynamics: a new peak effect in the critical current occurring in the solid state just below the melting transition, and anisotropic pinning by planar defects

Phase diagrams of flux lattices with disorder

We review the prediction, made in a previous work [Phys. Rev. B 52 (1995)], that the phase diagram of type II superconductors consists of a topologically ordered Bragg glass phase at low fields undergoing a transition at higher fields into a vortex glass or a liquid. We estimate the position of the phase boundary using a Lindemann criterion. We find that the proposed phenomenology is compatible with recent experiments on superconductors.Comment: 7 pages 2 figures, uses epsfi

The effect of disorder on the critical points in the vortex phase diagram of YBCO

The effect of line disorder induced by heavy ion irradiation and of point disorder induced by proton and electron irradiation on the upper and lower critical points in the vortex phase diagram of YBCO is presented. The authors find that dilute line disorder induces a Bose glass transition at low fields which is replaced at the lower critical point by first order melting at higher fields. Strong pinning point defects raise the lower critical point, while weak pinning point defects have little or no effect on the lower critical point. The upper critical point is lowered by point disorder, but raised by line disorder. First order melting is suppressed by point disorder in two ways, by lowering of the upper critical point only for weak point pins, or by merging of the upper and lower critical points for strong point pins. The differing responses of the upper and lower critical points to line and point disorder can be understood in a picture of transverse and longitudinal spatial fluctuations