302 research outputs found
Androgen Deprivation Therapy Potentiates the Efficacy of Vascular Targeted Photodynamic Therapy of Prostate Cancer Xenografts
WST11 vascular targeted photodynamic therapy (VTP) is a local ablation approach relying upon rapid, free radical-mediated destruction of tumor vasculature. A phase III trial showed that VTP significantly reduced disease progression when compared with active surveillance in patients with low-risk prostate cancer. The aim of this study was to identify a druggable pathway that could be combined with VTP to improve its efficacy and applicability to higher risk prostate cancer tumors. Transcriptome analysis of VTP-treated tumors (LNCaP-AR xenografts) was used to identify a candidate pathway for combination therapy. The efficacy of the combination therapy was assessed in mice bearing LNCaP-AR or VCaP tumors. Gene set enrichment analysis identifies the enrichment of androgen-responsive gene sets within hours after VTP treatment, suggesting that the androgen receptor (AR) may be a viable target in combination with VTP. We tested this hypothesis in mice bearing LNCaP-AR xenograft tumors by using androgen deprivation therapy (ADT), degarelix, in combination with VTP. Compared with either ADT or VTP alone, a single dose of degarelix in concert with VTP significantly inhibited tumor growth. A sharp decline in serum prostate-specific antigen (PSA) confirmed AR inhibition in this group. Tumors treated by VTP and degarelix displayed intense terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining 7 days after treatment, supporting an increased apoptotic frequency underlying the effect on tumor inhibition. Improvement of local tumor control following androgen deprivation combined with VTP provides the rationale and preliminary protocol parameters for clinical trials in patients presented with locally advanced prostate cancer.
Nucleation in Systems with Elastic Forces
Systems with long-range interactions when quenced into a metastable state
near the pseudo-spinodal exhibit nucleation processes that are quite different
from the classical nucleation seen near the coexistence curve. In systems with
long-range elastic forces the description of the nucleation process can be
quite subtle due to the presence of bulk/interface elastic compatibility
constraints. We analyze the nucleation process in a simple 2d model with
elastic forces and show that the nucleation process generates critical droplets
with a different structure than the stable phase. This has implications for
nucleation in many crystal-crystal transitions and the structure of the final
state
Avalanches in Breakdown and Fracture Processes
We investigate the breakdown of disordered networks under the action of an
increasing external---mechanical or electrical---force. We perform a mean-field
analysis and estimate scaling exponents for the approach to the instability. By
simulating two-dimensional models of electric breakdown and fracture we observe
that the breakdown is preceded by avalanche events. The avalanches can be
described by scaling laws, and the estimated values of the exponents are
consistent with those found in mean-field theory. The breakdown point is
characterized by a discontinuity in the macroscopic properties of the material,
such as conductivity or elasticity, indicative of a first order transition. The
scaling laws suggest an analogy with the behavior expected in spinodal
nucleation.Comment: 15 pages, 12 figures, submitted to Phys. Rev. E, corrected typo in
authors name, no changes to the pape
Critical behavior of a fluid in a disordered porous matrix: An Ornstein-Zernike approach
Using a liquid-state approach based on Ornstein-Zernike equations, we study
the behavior of a fluid inside a porous disordered matrix near the liquid-gas
critical point.The results obtained within various standard approximation
schemes such as lowest-order -ordering and the mean-spherical
approximation suggest that the critical behavior is closely related to that of
the random-field Ising model (RFIM).Comment: 10 pages, revtex, to appear in Physical Review Letter
Clusters and Fluctuations at Mean-Field Critical Points and Spinodals
We show that the structure of the fluctuations close to spinodals and
mean-field critical points is qualitatively different than the structure close
to non-mean-field critical points. This difference has important implications
for many areas including the formation of glasses in supercooled liquids. In
particular, the divergence of the measured static structure function in
near-mean-field systems close to the glass transition is suppressed relative to
the mean-field prediction in systems for which a spatial symmetry is broken.Comment: 5 pages, 1 figur
Chronic lymphocytic leukaemia: the role of T cells in a B cell disease
Chronic lymphocytic leukaemia (CLL) has long been thought to be an immunosuppressive disease and abnormalities in Tâcell subset distribution and function have been observed in many studies. However, the role of T cells (if any) in disease progression remains unclear and has not been directly studied. This has changed with the advent of new therapies, such as chimeric antigen receptorâT cells, which actively use retargeted patientâderived T cells as âliving drugsâ for CLL. However complete responses are relatively low (~26%) and recent studies have suggested the differentiation status of patient T cells before therapy may influence efficacy. Nonâchemotherapeutic drugs, such as idelalisib and ibrutinib, also have an impact on T cell populations in CLL patients. This review will highlight what is known about T cells in CLL during disease progression and after treatment, and discuss the prospects of using T cells as predictive biomarkers for immune status and response to therapy
The genetic insulator RiboJ increases expression of insulated genes
A primary objective of synthetic biology is the construction of genetic circuits with behaviors that can be predicted based on the properties of the constituent genetic parts from which they are built. However a significant issue in the construction of synthetic genetic circuits is a phenomenon known as context dependence in which the behavior of a given part changes depending on the choice of adjacent or nearby parts. Interactions between parts compromise the modularity of the circuit, impeding the implementation of predictable genetic constructs. To address this issue, investigators have devised genetic insulators that prevent these unintended context-dependent interactions between neighboring parts. One of the most commonly used insulators in bacterial systems is the self-cleaving ribozyme RiboJ. Despite its utility as an insulator, there has been no systematic quantitative assessment of the effect of RiboJ on the expression level of downstream genetic parts. Here, we characterized the impact of insulation with RiboJ on expression of a reporter gene driven by a promoter from a library of 24 frequently employed constitutive promoters in an Escherichia coli model system. We show that, depending on the strength of the promoter, insulation with RiboJ increased protein abundance between twofold and tenfold and increased transcript abundance by an average of twofold. This result demonstrates that genetic insulators in E. coli can impact the expression of downstream genes, information that is essential for the design of predictable genetic circuits and constructs
The genetic insulator RiboJ increases expression of insulated genes
A primary objective of synthetic biology is the construction of genetic circuits with behaviors that can be predicted based on the properties of the constituent genetic parts from which they are built. However a significant issue in the construction of synthetic genetic circuits is a phenomenon known as context dependence in which the behavior of a given part changes depending on the choice of adjacent or nearby parts. Interactions between parts compromise the modularity of the circuit, impeding the implementation of predictable genetic constructs. To address this issue, investigators have devised genetic insulators that prevent these unintended context-dependent interactions between neighboring parts. One of the most commonly used insulators in bacterial systems is the self-cleaving ribozyme RiboJ. Despite its utility as an insulator, there has been no systematic quantitative assessment of the effect of RiboJ on the expression level of downstream genetic parts. Here, we characterized the impact of insulation with RiboJ on expression of a reporter gene driven by a promoter from a library of 24 frequently employed constitutive promoters in an Escherichia coli model system. We show that, depending on the strength of the promoter, insulation with RiboJ increased protein abundance between twofold and tenfold and increased transcript abundance by an average of twofold. This result demonstrates that genetic insulators in E. coli can impact the expression of downstream genes, information that is essential for the design of predictable genetic circuits and constructs
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