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

Supercooling across first-order phase transitions in vortex matter

Hysteresis in cycling through first-order phase transitions in vortex matter, akin to the well-studied phenomenon of supercooling of water, has been discussed in literature. Hysteresis can be seen while varying either temperature T or magnetic field H (and thus the density of vortices). Our recent work on phase transitions with two control variables shows that the observable region of metastability of the supercooled phase would depend on the path followed in H-T space, and will be larger when T is lowered at constant H compared to the case when H is lowered at constant T. We discuss the effect of isothermal field variations on metastable supercooled states produced by field-cooling. This path dependence is not a priori applicable to metastability caused by reduced diffusivity or hindered kinetics.Comment: Tex, 8 pages, 3 Postscripts figures. Submitted to Pramana - J. Physic

A Pancreatic Polypeptide-Producing Pancreatic Tumor Causing WDHA Syndrome

We report the case of a 46-year-old female patient with WDHA (watery diarrhea/hypokalemia/achlorhydria) syndrome caused by a pancreatic polypeptide-producing tumor in the head of the pancreas. Whereas VIP and other pancreatic endocrine hormones were in the normal range, only serum levels of pancreatic polypeptide were elevated. Imaging studies identified a pancreatic tumor in the head of the gland. After laparotomy, the tumor of 3 cm in size was enucleated. Final pathology documented a pancreatic endocrine tumor with immunohistochemical staining demonstrating the presence of pancreatic polypeptide. The patient remained cured after a follow-up of more than three years. The present case illustrates that, although rare, WDHA syndrome may be associated with a pancreatic polypeptide-secreting endocrine tumor of the pancreas

Simulation Studies on the Stability of the Vortex-Glass Order

The stability of the three-dimensional vortex-glass order in random type-II superconductors with point disorder is investigated by equilibrium Monte Carlo simulations based on a lattice XY model with a uniform field threading the system. It is found that the vortex-glass order, which stably exists in the absence of screening, is destroyed by the screenng effect, corroborating the previous finding based on the spatially isotropic gauge-glass model. Estimated critical exponents, however, deviate considerably from the values reported for the gauge-glass model.Comment: Minor modifications made, a few referenced added; to appear in J. Phys. Soc. Jpn. Vol.69 No.1 (2000

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

A new structural class of serine protease inhibitors revealed by the structure of the hirustasin–kallikrein complex

AbstractBackground: Hirustasin belongs to a class of serine protease inhibitors characterized by a well conserved pattern of cysteine residues. Unlike the closely related inhibitors, antistasin/ghilanten and guamerin, which are selective for coagulation factor Xa or neutrophil elastase, hirustasin binds specifically to tissue kallikrein. The conservation of the pattern of cysteine residues and the significant sequence homology suggest that these related inhibitors possess a similar three-dimensional structure to hirustasin.Results: The crystal structure of the complex between tissue kallikrein and hirustasin was analyzed at 2.4 Å resolution. Hirustasin folds into a brick-like structure that is dominated by five disulfide bridges and is sparse in secondary structural elements. The cysteine residues are connected in an abab cdecde pattern that causes the polypeptide chain to fold into two similar motifs. As a hydrophobic core is absent from hirustasin the disulfide bridges maintain the tertiary structure and present the primary binding loop to the active site of the protease. The general structural topography and disulfide connectivity of hirustasin has not previously been described.Conclusions: The crystal structure of the kallikrein–hirustasin complex reveals that hirustasin differs from other serine protease inhibitors in its conformation and its disulfide bond connectivity, making it the prototype for a new class of inhibitor. The disulfide pattern shows that the structure consists of two domains, but only the C-terminal domain interacts with the protease. The disulfide pattern of the N-terminal domain is related to the pattern found in other proteins. Kallikrein recognizes hirustasin by the formation of an antiparallel β sheet between the protease and the inhibitor. The P1 arginine binds in a deep negatively charged pocket of the enzyme. An additional pocket at the periphery of the active site accommodates the sidechain of the P4 valine

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

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

HIV, STI prevalence and risk behaviours among women selling sex in Lahore, Pakistan

<p>Abstract</p> <p>Background</p> <p>More than 340 million cases of curable sexually transmitted infections (STIs) were estimated to have occurred worldwide in 1995. Previous studies have shown that the presence of other concomitant STIs increases the likelihood of HIV transmission. The first national study of STIs conducted in Pakistan in 2004 revealed a high burden of STIs among women selling sex. The HIV epidemic in Pakistan has thus far followed the "Asian epidemic model". Earlier studies among women selling sex have shown a low prevalence of HIV coupled with a low level of knowledge about AIDS. The aim of our study was to estimate the prevalence of HIV and STIs, and assess knowledge and risk behaviours related to HIV/STI, among women selling sex in Lahore, Pakistan.</p> <p>Methods</p> <p>A total of 730 participants were recruited through respondent-driven sampling. The participants were women selling sex in three areas (referred to as "A", "B", and "C") of Lahore. A structured questionnaire addressing demographic information, sexual life history, sexual contacts, and knowledge and practices related to HIV/STI prevention was administered by face-to-face interview. Biological samples were obtained from all participants and tested for HIV, <it>Treponema pallidum</it>, <it>Neisseria gonorrhoeae</it>, <it>Chlamydia trachomatis </it>and <it>Trichomonas vaginalis</it>. Pearson's chi-square and multivariable logistic regression analysis were performed to test associations between potential risk factors and specified diagnosed infections.</p> <p>Results</p> <p>The prevalence of HIV infection was 0.7%, <it>T pallidum </it>4.5%, <it>N gonorrhoeae </it>7.5%, <it>C trachomatis </it>7.7% and <it>T vaginalis </it>5.1%. The participants had been selling sex for a median period of seven years and had a median of three clients per day. Sixty five percent of the participants reported that they "Always use condom". The median fee per sexual contact was Rs. 250 (3 Euro). Compared to Areas A and C, women selling sex in Area B had a significantly higher risk of chlamydial infection, gonorrhoea and trichomoniasis. Among the participants, 37% had correct knowledge about HIV/AIDS transmission and its prevention.</p> <p>Conclusions</p> <p>The prevalence of HIV was <1%, and of any other STI 18.5% among participating women selling sex in Lahore, Pakistan. A reasonably high condom use, a relatively low number of sexual partners, and a relatively low prevalence of STIs might have contributed to the low HIV prevalence.</p