An epigenetic reprogramming strategy to re-sensitize radioresistant prostate cancer cells

Radiotherapy is a mainstay of curative prostate cancer treatment, but risks of recurrence after treatment remain significant in locally advanced disease. Given that tumor relapse can be attributed to a population of cancer stem cells (CSC) that survives radiotherapy, analysis of this cell population might illuminate tactics to personalize treatment. However, this direction remains challenging given the plastic nature of prostate cancers following treatment. We show here that irradiating prostate cancer cells stimulates a durable upregulation of stem cell markers that epigenetically reprogram these cells. In both tumorigenic and radioresistant cell populations, a phenotypic switch occurred during a course of radiotherapy that was associated with stable genetic and epigenetic changes. Specifically, we found that irradiation triggered histone H3 methylation at the promoter of the CSC marker aldehyde dehydrogenase 1A1 (ALDH1A1), stimulating its gene transcription. Inhibiting this methylation event triggered apoptosis, promoted radiosensitization, and hindered tumorigenicity of radioresistant prostate cancer cells. Overall, our results suggest that epigenetic therapies may restore the cytotoxic effects of irradiation in radioresistant CSC populations

Summarizing performance for genome scale measurement of miRNA: reference samples and metrics

Background: The potential utility of microRNA as biomarkers for early detection of cancer and other diseases is being investigated with genome-scale profiling of differentially expressed microRNA. Processes for measurement assurance are critical components of genome-scale measurements. Here, we evaluated the utility of a set of total RNA samples, designed with between-sample differences in the relative abundance of miRNAs, as process controls. Results: Three pure total human RNA samples (brain, liver, and placenta) and two different mixtures of these components were evaluated as measurement assurance control samples on multiple measurement systems at multiple sites and over multiple rounds. In silico modeling of mixtures provided benchmark values for comparison with physical mixtures. Biomarker development laboratories using next-generation sequencing (NGS) or genome-scale hybridization assays participated in the study and returned data from the samples using their routine workflows. Multiplexed and single assay reverse-transcription PCR (RT-PCR) was used to confirm in silico predicted sample differences. Data visualizations and summary metrics for genome-scale miRNA profiling assessment were developed using this dataset, and a range of performance was observed. These metrics have been incorporated into an online data analysis pipeline and provide a convenient dashboard view of results from experiments following the described design. The website also serves as a repository for the accumulation of performance values providing new participants in the project an opportunity to learn what may be achievable with similar measurement processes. Conclusions: The set of reference samples used in this study provides benchmark values suitable for assessing genome-scale miRNA profiling processes. Incorporation of these metrics into an online resource allows laboratories to periodically evaluate their performance and assess any changes introduced into their measurement process

Guided vortex motion in superconductors with a square antidot lattice

We have measured the in-plane anisotropy of the vortex mobility in a thin Pb film with a square array of antidots. The Lorentz force, acting on the vortices, was rotated by adding two perpendicular currents and keeping the amplitude of the net current constant. One set of voltage probes was used to detect the vortex motion. We show that the pinning landscape provided by the square antidot lattice influences the vortex motion in two different ways. First, the modulus of the vortex velocity becomes angular dependent with a lower mobility along the diagonals of the pinning array. Second, the vortex displacement is preferentially parallel to the principal axes of the underlying pinning lattice, giving rise to a misalignment between the vortex velocity and the applied Lorentz force. We show that this anisotropic vortex motion is temperature dependent and progressively fades out when approaching the normal state.Comment: 5 pages, 4 figure

Pharmacodynamic evaluation of commonly prescribed oral antibiotics against respiratory bacterial pathogens

<p>Abstract</p> <p>Background</p> <p>Upper and lower respiratory tract infections (RTIs) account for a substantial portion of outpatient antibiotic utilization. However, the pharmacodynamic activity of commonly used oral antibiotic regimens has not been studied against clinically relevant pathogens. The objective of this study was to assess the probability of achieving the requisite pharmacodynamic exposure for oral antibacterial regimens commonly prescribed for RTIs in adults against bacterial isolates frequently involved in these processes (<it>S. pneumoniae</it>, <it>H. influenzae</it>, and <it>M. catharralis</it>).</p> <p>Methods</p> <p>Using a 5000-subject Monte Carlo simulation, the cumulative fractions of response (CFR), (i.e., probabilities of achieving requisite pharmacodynamic targets) for the most commonly prescribed oral antibiotic regimens, as determined by a structured survey of medical prescription patterns, were assessed against local respiratory bacterial isolates from adults in São Paulo collected during the same time period. Minimal inhibitory concentration (MIC) of 230 isolates of <it>Streptococcus pneumoniae </it>(103), <it>Haemophilus influenzae </it>(98), and <it>Moraxella catharralis </it>(29) from a previous local surveillance were used.</p> <p>Results</p> <p>The most commonly prescribed antibiotic regimens were azithromycin 500 mg QD, amoxicillin 500 mg TID, and levofloxacin 500 mg QD, accounting for 58% of the prescriptions. Varied doses of these agents, plus gatifloxacin, amoxicillin-clavulanate, moxifloxacin, and cefaclor made up the remaining regimens. Utilizing aggressive pharmacodynamic exposure targets, the only regimens to achieve greater than 90% CFR against all three pathogens were amoxicillin/amoxicillin-clavulanate 500 mg TID (> 91%), gatifloxacin 400 mg QD (100%), and moxifloxacin 400 mg QD (100%). Considering <it>S. pneumoniae </it>isolates alone, azithromycin 1000 mg QD also achieved greater than 90% CFR (91.3%).</p> <p>Conclusions</p> <p>The only regimens to achieve high CFR against all three pathogen populations in both scenarios were gatifloxacin 400 mg QD, moxifloxacin 400 mg QD, and amoxicillin-clavulanate 500 mg TID. These data suggest the need for reconsideration of empiric antibiotic regimen selection among adult patients with RTIs in the São Paulo area. Additionally, this type of study could be used to optimize prescribing patterns in specific regions in light of emerging resistance.</p

Affective responses as guides to category-based inferences

Initial nonconscious affective reactions to a target individual may influence a perceiver's selection from among descriptively plausible categories with which to organize his impression of the target. Specifically, a perceiver may be more likely to employ a category that is consistent, in affective tone, with the tone of his affective reaction. Subjects in two studies were exposed to photographs of faces of target individuals. Degree of preference for the faces was manipulated, outside of subjects' awareness, by varying the state of pupillary dilation. Participants in Study One reported that verbal descriptions that characterized positively (compared to negatively) evaluated category prototypes were more likely to be descriptive of targets with dilated pupils. Similarly, participants judged descriptions that characterized negatively (compared to positively) evaluated prototypes as more likely to be descriptive of targets with constricted pupils. In Study Two, subjects' recall of personality descriptions that were (evaluatively) inconsistent with their initial affective response to the target was superior to their recall of descriptions that were (evaluatively) consistent with the tone of their initial response. The data are interpreted as evidence for the importance of nonconscious affective reactions in guiding the process of impression formation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45360/1/11031_2004_Article_BF00992317.pd

Summarizing performance for genome scale measurement of miRNA: reference samples and metrics

Background: The potential utility of microRNA as biomarkers for early detection of cancer and other diseases is being investigated with genome-scale profiling of differentially expressed microRNA. Processes for measurement assurance are critical components of genome-scale measurements. Here, we evaluated the utility of a set of total RNA samples, designed with between-sample differences in the relative abundance of miRNAs, as process controls. Results: Three pure total human RNA samples (brain, liver, and placenta) and two different mixtures of these components were evaluated as measurement assurance control samples on multiple measurement systems at multiple sites and over multiple rounds. In silico modeling of mixtures provided benchmark values for comparison with physical mixtures. Biomarker development laboratories using next-generation sequencing (NGS) or genome-scale hybridization assays participated in the study and returned data from the samples using their routine workflows. Multiplexed and single assay reverse-transcription PCR (RT-PCR) was used to confirm in silico predicted sample differences. Data visualizations and summary metrics for genome-scale miRNA profiling assessment were developed using this dataset, and a range of performance was observed. These metrics have been incorporated into an online data analysis pipeline and provide a convenient dashboard view of results from experiments following the described design. The website also serves as a repository for the accumulation of performance values providing new participants in the project an opportunity to learn what may be achievable with similar measurement processes. Conclusions: The set of reference samples used in this study provides benchmark values suitable for assessing genome-scale miRNA profiling processes. Incorporation of these metrics into an online resource allows laboratories to periodically evaluate their performance and assess any changes introduced into their measurement process

Age and gender dependent heart rate circadian model development and performance verification on the proarrhythmic drug case study

BACKGROUND: There are two main reasons for drug withdrawals at the various levels of the development path – hepatic and cardiac toxicity. The latter one is mainly connected with the proarrhythmic potency and according to the present practice is supposed to be recognized at the pre-clinical (in vitro and animal in vivo) or clinical level (human in vivo studies). There are, although, some limitations to all the above mentioned methods which have led to novel in vitro – in vivo extrapolation methods being introduced. With the use of in silico implemented mathematical and statistical modelling it is possible to translate the in vitro findings into the human in vivo situation at the population level. Human physiology is influenced by many parameters and one of them which needs to be properly accounted for is a heart rate which follows the circadian rhythm. We described such phenomenon statistically which enabled the improved assessment of the drug proarrhythmic potency. METHODS: A publicly available data set describing the circadian changes of the heart rate of 18 healthy subjects, 5 males (average age 36, range 26–45) and 13 females (average age 34, range 20–50) was used for the heart rate model development. External validation was done with the use of a clinical research database containing heart rate measurements derived from 67 healthy subjects, 34 males and 33 females (average age 33, range 17–72). The developed heart rate model was then incorporated into the ToxComp platform to simulate the impact of circadian variation in the heart rate on QTc interval. The usability of the combined models was assessed with moxifloxacin (MOXI) as a model drug. RESULTS: The developed heart rate model fitted well, both to the training data set (RMSE = 128 ms and MAPE = 12.3%) and the validation data set (RMSE = 165 ms and MAPE = 17.1%). Simulations performed at the population level proved that the combination of the IVIVE platform and the population variability description allows for the precise prediction of the circadian variation of drugs proarrhythmic effect. CONCLUSIONS: It can be concluded that a flexible and practically useful model describing the heart rate circadian variation has been developed and its performance was verified