Telomerase inhibition by siRNA causes senescence and apoptosis in Barrett's adenocarcinoma cells: mechanism and therapeutic potential

BACKGROUND: In cancer cells, telomerase induction helps maintain telomere length and thereby bypasses senescence and provides enhanced replicative potential. Chemical inhibitors of telomerase have been shown to reactivate telomere shortening and cause replicative senescence and apoptotic cell death of tumor cells while having little or no effect on normal diploid cells. RESULTS: We designed siRNAs against two different regions of telomerase gene and evaluated their effect on telomere length, proliferative potential, and gene expression in Barrett's adenocarcinoma SEG-1 cells. The mixture of siRNAs in nanomolar concentrations caused a loss of telomerase activity that appeared as early as day 1 and was essentially complete at day 3. Inhibition of telomerase activity was associated with marked reduction in median telomere length and complete loss of detectable telomeres in more than 50% of the treated cells. Telomere loss caused senescence in 40% and apoptosis in 86% of the treated cells. These responses appeared to be associated with activation of DNA sensor HR23B and subsequent activation of p53 homolog p73 and p63 and E2F1. Changes in these gene regulators were probably the source of observed up-regulation of cell cycle inhibitors, p16 and GADD45. Elevated transcript levels of FasL, Fas and caspase 8 that activate death receptors and CARD 9 that interacts with Bcl10 and NFKB to enhance mitochondrial translocation and activation of caspase 9 were also observed. CONCLUSION: These studies show that telomerase siRNAs can cause effective suppression of telomerase and telomere shortening leading to both cell cycle arrest and apoptosis via mechanisms that include up-regulation of several genes involved in cell cycle arrest and apoptosis. Telomerase siRNAs may therefore be strong candidates for highly selective therapy for chemoprevention and treatment of Barrett's adenocarcinoma

QGP Susceptibilities from PNJL Model

An improved version of the PNJL model is used to calculate various thermodynamical quantities, {\it viz.}, quark number susceptibility, isospin susceptibility, specific heat, speed of sound and conformal measure. Comparison with Lattice data is found to be encouraging.Comment: 4 pages, 2 figures, poster presented at Quark Matter'0

The dChip survival analysis module for microarray data

International audienceBACKGROUND: Genome-wide expression signatures are emerging as potential marker for overall survival and disease recurrence risk as evidenced by recent commercialization of gene expression based biomarkers in breast cancer. Similar predictions have recently been carried out using genome-wide copy number alterations and microRNAs. Existing software packages for microarray data analysis provide functions to define expression-based survival gene signatures. However, there is no software that can perform survival analysis using SNP array data or draw survival curves interactively for expression-based sample clusters. RESULTS: We have developed the survival analysis module in the dChip software that performs survival analysis across the genome for gene expression and copy number microarray data. Built on the current dChip software's microarray analysis functions such as chromosome display and clustering, the new survival functions include interactive exploring of Kaplan-Meier (K-M) plots using expression or copy number data, computing survival p-values from the log-rank test and Cox models, and using permutation to identify significant chromosome regions associated with survival. CONCLUSIONS: The dChip survival module provides user-friendly way to perform survival analysis and visualize the results in the context of genes and cytobands. It requires no coding expertise and only minimal learning curve for thousands of existing dChip users. The implementation in Visual C++ also enables fast computation. The software and demonstration data are freely available at http://dchip-surv.chenglilab.org

Wakes in the quark-gluon plasma

Using the high temperature approximation we study, within the linear response theory, the wake in the quark-gluon plasma by a fast parton owing to dynamical screening in the space like region. When the parton moves with a speed less than the average speed of the plasmon, we find that the wake structure corresponds to a screening charge cloud traveling with the parton with one sign flip in the induced charge density resulting in a Lennard-Jones type potential in the outward flow with a short range repulsive and a long range attractive part. On the other hand if the parton moves with a speed higher than that of plasmon, the wake structure in the induced charge density is found to have alternate sign flips and the wake potential in the outward flow oscillates analogous to Cerenkov like wave generation with a Mach cone structure trailing the moving parton. The potential normal to the motion of the parton indicates a transverse flow in the system. We also calculate the potential due to a color dipole and discuss consequences of possible new bound states and $J/\psi$ suppression in the quark-gluon plasma.Comment: 20 pages, 14 figures (high resolution figures available with authors); version accepted for publication in Phys. Rev.

Distinguishing among Scalar Field Models of Dark Energy

We show that various scalar field models of dark energy predict degenerate luminosity distance history of the Universe and thus cannot be distinguished by supernovae measurements alone. In particular, models with a vanishing cosmological constant (the value of the potential at its minimum) are degenerate with models with a positive or negative cosmological constant whose magnitude can be as large as the critical density. Adding information from CMB anisotropy measurements does reduce the degeneracy somewhat but not significantly. Our results indicate that a theoretical prior on the preferred form of the potential and the field's initial conditions may allow to quantitatively estimate model parameters from data. Without such a theoretical prior only limited qualitative information on the form and parameters of the potential can be extracted even from very accurate data.Comment: 15 pages, 5 figure

Transcription factor-pathway co-expression analysis reveals cooperation between SP1 and ESR1 on dysregulating cell cycle arrest in non-hyperdiploid multiple myeloma

Multiple myeloma is a hematological cancer of plasma B-cells and remains incurable. Two major subtypes of myeloma, hyperdiploid (HMM) and non-hyperdiploid myeloma (NHMM), have distinct chromosomal alterations and different survival outcomes. Transcription factors (TrFs) have been implicated in myeloma oncogenesis but their dysregulation in myeloma subtypes are less studied. Here we develop a TrF-pathway co-expression analysis to identify altered co-expression between two sample types. We apply the method to the two myeloma subtypes and the cell cycle arrest pathway, which is significantly differentially expressed between the two subtypes. We find that TrFs MYC, NF-κB and HOXA9 have significantly lower co-expression with cell cycle arrest in HMM, co-occurring with their over-activation in HMM. In contrast, TrFs ESR1, SP1 and E2F1 have significantly lower co-expression with cell cycle arrest in NHMM. SP1 ChIP targets are enriched by cell cycle arrest genes. These results motivate a cooperation model of ESR1 and SP1 in regulating cell cycle arrest, and a hypothesis that their over-activation in NHMM disrupts proper regulation of cell cycle arrest. Co-targeting ESR1 and SP1 shows a synergistic effect on inhibiting myeloma proliferation in NHMM cell lines. Therefore, studying TrF-pathway co-expression dysregulation in human cancers facilitates forming novel hypotheses towards clinical utility

Endocrine-disrupting alkylphenols are widespread in the blood of lobsters from southern New England and adjacent offshore areas

Author Posting. © National Shellfisheries Association , 2012. This article is posted here by permission of National Shellfisheries Association for personal use, not for redistribution. The definitive version was published in Journal of Shellfish Research 31 (2012): 563-571, doi:10.2983/035.031.0216.Endocrine-disrupting pollutants in rivers and oceans represent a poorly understood but potentially serious threat to the integrity of aquatic and coastal ecosystems. We surveyed the hemolymph of lobsters from across southern New England and adjacent offshore areas for 3 endocrine-disrupting alkylphenols. We found all 3 compounds in hemolymph from every year and almost every region sampled. Prevalence of contamination varied significantly between regions, ranging from 45% of lobsters from southern Massachusetts to 17% of lobsters from central Long Island Sound. Mean contamination levels varied significantly as a function of region, year sampled, and collection trip, and were highest overall in lobsters from western Long Island Sound and lowest in lobsters from central Long Island Sound. Surprisingly, lobsters from offshore areas were not less contaminated than lobsters from inshore areas. Contamination levels also did not vary as a function of lobster size or shell disease signs. Contaminated lobsters held in the laboratory did not retain alkylphenols, suggesting that hemolymph contamination levels represent recent, rather than long-term, exposure. Our data set is the first, to our knowledge, to survey endocrine-disrupting contaminants in a population across such a broad temporal and spatial scale. We show that alkylphenol contamination is a persistent, widespread, but environmentally heterogeneous problem in lobster populations in southern New England and adjacent offshore areas. Our work raises serious questions about the prevalence and accumulation of these endocrine-disrupting pollutants in an important fishery species.This work was supported by the National Marine Fisheries Service as the New England Lobster Research Initiative: Lobster Shell Disease under NOAA grant NA06NMF4720100 to the University of Rhode Island Fisheries Center

Low Energy Light Yield of Fast Plastic Scintillators

Compact neutron imagers using double-scatter kinematic reconstruction are being designed for localization and characterization of special nuclear material. These neutron imaging systems rely on scintillators with a rapid prompt temporal response as the detection medium. As n-p elastic scattering is the primary mechanism for light generation by fast neutron interactions in organic scintillators, proton light yield data are needed for accurate assessment of scintillator performance. The proton light yield of a series of commercial fast plastic organic scintillators---EJ-200, EJ-204, and EJ-208---was measured via a double time-of-flight technique at the 88-Inch Cyclotron at Lawrence Berkeley National Laboratory. Using a tunable deuteron breakup neutron source, target scintillators housed in a dual photomultiplier tube configuration, and an array of pulse-shape-discriminating observation scintillators, the fast plastic scintillator light yield was measured over a broad and continuous energy range down to proton recoil energies of approximately 50 keV. This work provides key input to event reconstruction algorithms required for utilization of these materials in emerging neutron imaging modalities.Comment: 15 pages, 6 figure

Skewness in the Cosmic Microwave Background Anisotropy from Inflationary Gravity Wave Background

In the context of inflationary scenarios, the observed large angle anisotropy of the Cosmic Microwave Background (CMB) temperature is believed to probe the primordial metric perturbations from inflation. Although the perturbations from inflation are expected to be gaussian random fields, there remains the possibility that nonlinear processes at later epochs induce ``secondary'' non-gaussian features in the corresponding CMB anisotropy maps. The non-gaussianity induced by nonlinear gravitational instability of scalar (density) perturbations has been investigated in existing literature. In this paper, we highlight another source of non-gaussianity arising out of higher order scattering of CMB photons off the metric perturbations. We provide a simple and elegant formalism for deriving the CMB temperature fluctuations arising due to the Sachs-Wolfe effect beyond the linear order. In particular, we derive the expression for the second order CMB temperature fluctuations. The multiple scattering effect pointed out in this paper leads to the possibility that tensor metric perturbation, i.e., gravity waves (GW) which do not exhibit gravitational instability can still contribute to the skewness in the CMB anisotropy maps. We find that in a flat $\Omega =1$ universe, the skewness in CMB contributed by gravity waves via multiple scattering effect is comparable to that from the gravitational instability of scalar perturbations for equal contribution of the gravity waves and scalar perturbations to the total rms CMB anisotropy. The secondary skewness is found to be smaller than the cosmic variance leading to the conclusion that inflationary scenarios do predict that the observed CMB anisotropy should be statistically consistent with a gaussian random distribution.Comment: 10 pages, Latex (uses revtex), 1 postscript figure included. Accepted for publication in Physical Review

Bremsstrahlung from an Equilibrating Quark-Gluon Plasma

The photon production rate from a chemically equilibrating quark-gluon plasma likely to be produced at RHIC (BNL) and LHC (CERN) energies is estimated taking into account bremsstrahlung. The plasma is assumed to be in local thermal equilibrium, but with a phase space distribution that deviates from the Fermi or Bose distribution by space-time dependent factors (fugacities). The photon spectrum is obtained by integrating the photon rate over the space-time history of the plasma, adopting a boost invariant cylindrically symmetric transverse expansion of the system with different nuclear profile functions. Initial conditions obtained from a self-screened parton cascade calculation and, for comparison, from the HIJING model are used. Compared to an equilibrated plasma at the same initial energy density, taken from the self-screened parton cascade, a moderate suppression of the photon yield by a factor of one to five depending on the collision energy and the photon momentum is observed. The individual contributions to the photon production, however, are completely different in the both scenarios.Comment: 14 pages, 4 figures, shortened version to be published in Phys. Rev.