4,099 research outputs found
Copper signaling axis as a target for prostate cancer therapeutics.
Previously published reports indicate that serum copper levels are elevated in patients with prostate cancer and that increased copper uptake can be used as a means to image prostate tumors. It is unclear, however, to what extent copper is required for prostate cancer cell function as we observed only modest effects of chelation strategies on the growth of these cells in vitro. With the goal of exploiting prostate cancer cell proclivity for copper uptake, we developed a "conditional lethal" screen to identify compounds whose cytotoxic actions were manifested in a copper-dependent manner. Emerging from this screen was a series of dithiocarbamates, which, when complexed with copper, induced reactive oxygen species-dependent apoptosis of malignant, but not normal, prostate cells. One of the dithiocarbamates identified, disulfiram (DSF), is an FDA-approved drug that has previously yielded disappointing results in clinical trials in patients with recurrent prostate cancer. Similarly, in our studies, DSF alone had a minimal effect on the growth of prostate cancer tumors when propagated as xenografts. However, when DSF was coadministered with copper, a very dramatic inhibition of tumor growth in models of hormone-sensitive and of castrate-resistant disease was observed. Furthermore, we determined that prostate cancer cells express high levels of CTR1, the primary copper transporter, and additional chaperones that are required to maintain intracellular copper homeostasis. The expression levels of most of these proteins are increased further upon treatment of androgen receptor (AR)-positive prostate cancer cell lines with androgens. Not surprisingly, robust CTR1-dependent uptake of copper into prostate cancer cells was observed, an activity that was accentuated by activation of AR. Given these data linking AR to intracellular copper uptake, we believe that dithiocarbamate/copper complexes are likely to be effective for the treatment of patients with prostate cancer whose disease is resistant to classical androgen ablation therapies
Mean-Payoff Optimization in Continuous-Time Markov Chains with Parametric Alarms
Continuous-time Markov chains with alarms (ACTMCs) allow for alarm events
that can be non-exponentially distributed. Within parametric ACTMCs, the
parameters of alarm-event distributions are not given explicitly and can be
subject of parameter synthesis. An algorithm solving the -optimal
parameter synthesis problem for parametric ACTMCs with long-run average
optimization objectives is presented. Our approach is based on reduction of the
problem to finding long-run average optimal strategies in semi-Markov decision
processes (semi-MDPs) and sufficient discretization of parameter (i.e., action)
space. Since the set of actions in the discretized semi-MDP can be very large,
a straightforward approach based on explicit action-space construction fails to
solve even simple instances of the problem. The presented algorithm uses an
enhanced policy iteration on symbolic representations of the action space. The
soundness of the algorithm is established for parametric ACTMCs with
alarm-event distributions satisfying four mild assumptions that are shown to
hold for uniform, Dirac and Weibull distributions in particular, but are
satisfied for many other distributions as well. An experimental implementation
shows that the symbolic technique substantially improves the efficiency of the
synthesis algorithm and allows to solve instances of realistic size.Comment: This article is a full version of a paper accepted to the Conference
on Quantitative Evaluation of SysTems (QEST) 201
Quantitative immuno-mass spectrometry imaging of skeletal muscle dystrophin
Emerging and promising therapeutic interventions for Duchenne muscular dystrophy (DMD) are confounded by the challenges of quantifying dystrophin. Current approaches have poor precision, require large amounts of tissue, and are difficult to standardize. This paper presents an immuno-mass spectrometry imaging method using gadolinium (Gd)-labeled anti-dystrophin antibodies and laser ablation-inductively coupled plasma-mass spectrometry to simultaneously quantify and localize dystrophin in muscle sections. Gd is quantified as a proxy for the relative expression of dystrophin and was validated in murine and human skeletal muscle sections following k-means clustering segmentation, before application to DMD patients with different gene mutations where dystrophin expression was measured up to 100 µg kg−1 Gd. These results demonstrate that immuno-mass spectrometry imaging is a viable approach for pre-clinical to clinical research in DMD. It rapidly quantified relative dystrophin in single tissue sections, efficiently used valuable patient resources, and may provide information on drug efficacy for clinical translation
Steady-state modulation of voltage-gated K+ channels in rat arterial smooth muscle by cyclic AMP-dependent protein kinase and protein phosphatase 2B
Voltage-gated potassium channels (Kv) are important regulators of membrane potential in vascular smooth muscle cells, which is integral to controlling intracellular Ca2+ concentration and regulating vascular tone. Previous work indicates that Kv channels can be modulated by receptor-driven alterations of cyclic AMP-dependent protein kinase (PKA) activity. Here, we demonstrate that Kv channel activity is maintained by tonic activity of PKA. Whole-cell recording was used to assess the effect of manipulating PKA signalling on Kv and ATP-dependent K+ channels of rat mesenteric artery smooth muscle cells. Application of PKA inhibitors, KT5720 or H89, caused a significant inhibition of Kv currents. Tonic PKA-mediated activation of Kv appears maximal as application of isoprenaline (a β-adrenoceptor agonist) or dibutyryl-cAMP failed to enhance Kv currents. We also show that this modulation of Kv by PKA can be reversed by protein phosphatase 2B/calcineurin (PP2B). PKA-dependent inhibition of Kv by KT5720 can be abrogated by pre-treatment with the PP2B inhibitor cyclosporin A, or inclusion of a PP2B auto-inhibitory peptide in the pipette solution. Finally, we demonstrate that tonic PKA-mediated modulation of Kv requires intact caveolae. Pre-treatment of the cells with methyl-β-cyclodextrin to deplete cellular cholesterol, or adding caveolin-scaffolding domain peptide to the pipette solution to disrupt caveolae-dependent signalling each attenuated PKA-mediated modulation of the Kv current. These findings highlight a novel, caveolae-dependent, tonic modulatory role of PKA on Kv channels providing new insight into mechanisms and the potential for pharmacological manipulation of vascular tone
Phase 2 study of combination SPI-1620 with docetaxel as second-line advanced biliary tract cancer treatment
The Architectural Design Rules of Solar Systems based on the New Perspective
On the basis of the Lunar Laser Ranging Data released by NASA on the Silver
Jubilee Celebration of Man Landing on Moon on 21st July 1969-1994, theoretical
formulation of Earth-Moon tidal interaction was carried out and Planetary
Satellite Dynamics was established. It was found that this mathematical
analysis could as well be applied to Star and Planets system and since every
star could potentially contain an extra-solar system, hence we have a large
ensemble of exoplanets to test our new perspective on the birth and evolution
of solar systems. Till date 403 exoplanets have been discovered in 390
extra-solar systems. I have taken 12 single planet systems, 4 Brown Dwarf -
Star systems and 2 Brown Dwarf pairs. Following architectural design rules are
corroborated through this study of exoplanets. All planets are born at inner
Clarke Orbit what we refer to as inner geo-synchronous orbit in case of
Earth-Moon System. By any perturbative force such as cosmic particles or
radiation pressure, the planet gets tipped long of aG1 or short of aG1. Here
aG1 is inner Clarke Orbit. The exoplanet can either be launched on death spiral
as CLOSE HOT JUPITERS or can be launched on an expanding spiral path as the
planets in our Solar System are. It was also found that if the exo-planet are
significant fraction of the host star then those exo-planets rapidly migrate
from aG1 to aG2 and have very short Time Constant of Evolution as Brown Dwarfs
have. This vindicates our basic premise that planets are always born at inner
Clarke Orbit. This study vindicates the design rules which had been postulated
at 35th COSPAR Scientific Assembly in 2004 at Paris, France, under the title
,New Perspective on the Birth & Evolution of Solar Systems.Comment: This paper has been reported to Earth,Moon and Planets Journal as
MOON-S-09-0007
Chiral Polymerization in Open Systems From Chiral-Selective Reaction Rates
We investigate the possibility that prebiotic homochirality can be achieved
exclusively through chiral-selective reaction rate parameters without any other
explicit mechanism for chiral bias. Specifically, we examine an open network of
polymerization reactions, where the reaction rates can have chiral-selective
values. The reactions are neither autocatalytic nor do they contain explicit
enantiomeric cross-inhibition terms. We are thus investigating how rare a set
of chiral-selective reaction rates needs to be in order to generate a
reasonable amount of chiral bias. We quantify our results adopting a
statistical approach: varying both the mean value and the rms dispersion of the
relevant reaction rates, we show that moderate to high levels of chiral excess
can be achieved with fairly small chiral bias, below 10%. Considering the
various unknowns related to prebiotic chemical networks in early Earth and the
dependence of reaction rates to environmental properties such as temperature
and pressure variations, we argue that homochirality could have been achieved
from moderate amounts of chiral selectivity in the reaction rates.Comment: 15 pages, 6 figures, accepted for publication in Origins of Life and
Evolution of Biosphere
Response: Infant EEG activity as a biomarker for autism: A promising approach or a false promise?
Light smoking at base-line predicts a higher mortality risk to women than to men; evidence from a cohort with long follow-up
BACKGROUND: There is conflicting evidence as to whether smoking is more harmful to women than to men. The UK Cotton Workers’ Cohort was recruited in the 1960s and contained a high proportion of men and women smokers who were well matched in terms of age, job and length of time in job. The cohort has been followed up for 42 years. METHODS: Mortality in the cohort was analysed using an individual relative survival method and Cox regression. Whether smoking, ascertained at baseline in the 1960s, was more hazardous to women than to men was examined by estimating the relative risk ratio women to men, smokers to never smoked, for light (1–14), medium (15–24), heavy (25+ cigarettes per day) and former smoking. RESULTS: For all-cause mortality relative risk ratios were 1.35 for light smoking at baseline (95% CI 1.07-1.70), 1.15 for medium smoking (95% CI 0.89-1.49) and 1.00 for heavy smoking (95% CI 0.63-1.61). Relative risk ratios for light smoking at baseline for circulatory system disease was 1.42 (95% CI 1.01 to 1.98) and for respiratory disease was 1.89 (95% CI 0.99 to 3.63). Heights of participants provided no explanation for the gender difference. CONCLUSIONS: Light smoking at baseline was shown to be significantly more hazardous to women than to men but the effect decreased as consumption increased indicating a dose response relationship. Heavy smoking was equally hazardous to both genders. This result may help explain the conflicting evidence seen elsewhere. However gender differences in smoking cessation may provide an alternative explanation
Attention deficit hyperactivity disorder symptomatology and pediatric obesity: Psychopathology or sleep deprivation?
The relationship between attention deficit hyperactivity disorder (ADHD) and obesity in children has received considerable attention in recent years. However, the literature currently overlooks the potential causal and maintaining role that sleep problems may play in this relationship. Using a biopsychosocial framework, this article highlights how sleep problems impact the biological, psychological, and social aspects of both ADHD symptomatology and obesity. An in-depth examination of this model illustrates the imperative need for future research and clinical practice to recognize and explore the role sleep has in the link between obesity and ADHD symptomatology
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