575 research outputs found

    Retroviral Genotoxicity

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    A novel approach to identify driver genes involved in androgen-independent prostate cancer

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    Abstract Background Insertional mutagenesis screens have been used with great success to identify oncogenes and tumor suppressor genes. Typically, these screens use gammaretroviruses (γRV) or transposons as insertional mutagens. However, insertional mutations from replication-competent γRVs or transposons that occur later during oncogenesis can produce passenger mutations that do not drive cancer progression. Here, we utilized a replication-incompetent lentiviral vector (LV) to perform an insertional mutagenesis screen to identify genes in the progression to androgen-independent prostate cancer (AIPC). Methods Prostate cancer cells were mutagenized with a LV to enrich for clones with a selective advantage in an androgen-deficient environment provided by a dysregulated gene(s) near the vector integration site. We performed our screen using an in vitro AIPC model and also an in vivo xenotransplant model for AIPC. Our approach identified proviral integration sites utilizing a shuttle vector that allows for rapid rescue of plasmids in E. coli that contain LV long terminal repeat (LTR)-chromosome junctions. This shuttle vector approach does not require PCR amplification and has several advantages over PCR-based techniques. Results Proviral integrations were enriched near prostate cancer susceptibility loci in cells grown in androgen-deficient medium (p < 0.001), and five candidate genes that influence AIPC were identified; ATPAF1, GCOM1, MEX3D, PTRF, and TRPM4. Additionally, we showed that RNAi knockdown of ATPAF1 significantly reduces growth (p < 0.05) in androgen-deficient conditions. Conclusions Our approach has proven effective for use in PCa, identifying a known prostate cancer gene, PTRF, and also several genes not previously associated with prostate cancer. The replication-incompetent shuttle vector approach has broad potential applications for cancer gene discovery, and for interrogating diverse biological and disease processes.http://deepblue.lib.umich.edu/bitstream/2027.42/109477/1/12943_2014_Article_1323.pd

    Effectiveness of community-links practitioners in areas of high socioeconomic deprivation

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    PURPOSE: To assess the effect of a primary care–based community-links practitioner (CLP) intervention on patients’ quality of life and well-being. METHODS: Quasi-experimental cluster-randomized controlled trial in socioeconomically deprived areas of Glasgow, Scotland. Adult patients (aged 18 years or older) referred to CLPs in 7 intervention practices were compared with a random sample of adult patients from 8 comparison practices at baseline and 9 months. Primary outcome: health-related quality of life (EQ-5D-5L, a standardized measure of self-reported health-related quality of life that assesses 5 dimensions at 5 levels of severity). Secondary outcomes: well-being (Investigating Choice Experiments for the Preferences of Older People Capability Measure for Adults [ICECAP-A]), depression (Hospital Anxiety and Depression Scale, Depression [HADS-D]), anxiety (Hospital Anxiety and Depression Scale, Anxiety [HADS-A]), and self-reported exercise. Multilevel, multiregression analyses adjusted for baseline differences. Patients were not blinded to the intervention, but outcome analysis was masked. RESULTS: Data were collected on 288 and 214 (74.3%) patients in the intervention practices at baseline and follow-up, respectively, and on 612 and 561 (92%) patients in the comparison practices. Intention-to-treat analysis found no differences between the 2 groups for any outcome. In subgroup analyses, patients who saw the CLP on 3 or more occasions (45% of those referred) had significant improvements in EQ-5D-5L, HADS-D, HADS-A, and exercise levels. There was a high positive correlation between CLP consultation rates and patient uptake of suggested community resources. CONCLUSIONS: We were unable to prove the effectiveness of referral to CLPs based in primary care in deprived areas for improving patient outcomes. Future efforts to boost uptake and engagement could improve overall outcomes, although the apparent improvements in those who regularly saw the CLPs may be due to reverse causality. Further research is needed before wide-scale deployment of this approach

    Internal Carotid Artery Redundancy is Significantly Associated With Dissection.

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    BACKGROUND AND PURPOSE: Redundant internal carotid arteries have been considered a risk factor in tonsillectomy, adenoidectomy, and surgical treatment of peritonsillar abscess and also a potentially treatable cause of stroke. However, an association between internal carotid artery redundancy and spontaneous dissection has not yet been clearly demonstrated. METHODS: We reviewed, for spontaneous carotid artery dissection, records of all patients admitted to our institution during the period from 1986 through 1992 with the diagnosis of stroke or transient ischemic attack. We also reviewed 108 percutaneous cerebral arteriograms performed between September 1992 and December 1992 for presence of carotid artery redundancies. RESULTS: Thirteen patients exhibited spontaneous dissection. Of these, 8 of 13 (62%) patients and 13 of 20 (65%) internal carotid arteries, viewed to the siphon, had significant redundancies, kinks, coils, or loops. Of 108 consecutive arteriograms of patients without dissection, in which 187 internal carotid arteries were viewed to the siphon, there were 20 (19%) patients and 22 (12%) of 187 vessels with significant redundancy. Five patients in the dissection group and 2 in the nondissection group had bilateral internal carotid artery redundancy (P = .0019 and P = .0001, respectively). CONCLUSIONS: We found a significant correlation between internal carotid artery redundancy and dissection, particularly if redundancy is present bilaterally

    Digital Silicon Photomultipliers with OR/XOR Pulse Combining Techniques

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    A recently proposed XOR-based digital silicon photomultiplier (dSiPM) is compared against the OR-based counterpart. We show experimental data from a set of single-photon avalanche diode (SPAD) pixel arrays in 130-nm CMOS process with selectable OR tree and XOR tree for direct comparison. We demonstrate how XOR-based dSiPMs solve the limitation caused by monostable circuits and reach higher maximum count rates compared with optimized OR-based dSiPMs. The increased throughput of the SPAD array allows higher sampling rates for the digitization of the light signal enhancing dynamic range and linearity

    Internet Gaming Disorder in children and adolescents

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    The American Psychiatric Association recently included Internet gaming disorder (IGD) as a potential diagnosis, recommending that further study be conducted to help illuminate it more clearly. This paper is a summary of the review undertaken by the IGD Working Group as part of the 2015 National Academy of Sciences Sackler Colloquium on Digital Media and Developing Minds. By using measures based on or similar to the IGD definition, we found that prevalence rates range between ∼1% and 9%, depending on age, country, and other sample characteristics. The etiology of IGD is not well-understood at this time, although it appears that impulsiveness and high amounts of time gaming may be risk factors. Estimates for the length of time the disorder can last vary widely, but it is unclear why. Although the authors of several studies have demonstrated that IGD can be treated, no randomized controlled trials have yet been published, making any definitive statements about treatment impossible. IGD does, therefore, appear to be an area in which additional research is clearly needed. We discuss several of the critical questions that future research should address and provide recommendations for clinicians, policy makers, and educators on the basis of what we know at this time

    A SPAD-Based QVGA Image Sensor for Single-Photon Counting and Quanta Imaging

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    A CMOS single-photon avalanche diode (SPAD)-based quarter video graphics array image sensor with 8-μm pixel pitch and 26.8% fill factor (FF) is presented. The combination of analog pixel electronics and scalable shared-well SPAD devices facilitates high-resolution, high-FF SPAD imaging arrays exhibiting photon shot-noise-limited statistics. The SPAD has 47 counts/s dark count rate at 1.5 V excess bias (EB), 39.5% photon detection probability (PDP) at 480 nm, and a minimum of 1.1 ns dead time at 1 V EB. Analog single-photon counting imaging is demonstrated with maximum 14.2-mV/SPAD event sensitivity and 0.06e- minimum equivalent read noise. Binary quanta image sensor (QIS) 16-kframes/s real-time oversampling is shown, verifying single-photon QIS theory with 4.6× overexposure latitude and 0.168e- read noise

    Analysis of Photon Detection Efficiency and Dynamic Range in SPAD based Visible Light Receivers

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    We investigate the photon detection efficiency (PDE) and the dynamic range for digital silicon photomultipliers (dSiPMs) over a selection of design parameters: dSiPM unit cell dead time, PDE, unit cell area and fill factor, number of cells, and total dSiPM active area. Two receiver scaling scenarios are con-sidered: varying the number of cells for 1) a fixed unit cell area or 2) a fixed total dSiPM area. Theoretical and simulated results are confirmed with experimental data from a selection of dSiPMs realised on a test chip in130-nm CMOS process
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