The Role Of Mouse Mammary Tumor Virus In The Induction And Progression Of Mouse Mammary Tumors

Mouse mammary tumor virus (MMTV) is a retrovirus which causes mammary tumors in many strains of mice. An essential part of the viral life cycle involves the integration of a double-stranded DNA provirus into the host cell genome. Tumorigenesis is thought to be mediated by such integrated proviruses.;Restriction endonuclease analysis of the DNA from a series of cell sublines from a single MMTV-induced mammary adenocarcinoma revealed that the original tumor was composed of tumorigenic and nontumorigenic cells whose proviral content could not be correlated with tumorigenicity. The tumorigenic sublines however contained a single provirus which was correlated with tumorigenicity. The tumorigenic potential of MMTV proviruses therefore depends on the site of integration.;In a second study it was shown that the mode of action of a germinally-transmitted locus of GR mice, Mtv-2, was through the generation of proviruses which activated the putative mammary proto-oncogenes int-1 and int-2.;It was also shown that a series of chemically or hormonally induced hyperplastic alveolar nodule outgrowth lines each had an integrated MMTV provirus at the same site in the genome. This locus was shown to be different from the putative mammary proto-oncogenes int-1 and int-2. Since this locus is associated with hyperplasia (a preneoplastic condition), it has been designated int-H.;A portion of the int-H locus was molecularly cloned in a lamba phage vector-host system designed to prevent the deletion of those sequences capable of forming secondary structures. DNA from the int-H region has homology to a family of sequences in rat and human as well as mouse DNA. Transcripts from this region were detected in normal midpregnant mammary tissue as well as in preneoplastic tissue. This locus may code for a regulatory molecule. Proviral disruption of int-H regulation may predispose cells to becoming tumorigenic

Virtual multichannel SAR for ground moving target imaging

Slow moving ground targets are invisible within synthetic aperture radar (SAR) images since they appear defocused and their backscattered signal completely overlap the focused ground return. In order for this targets to be detected and refocused the availability of some spatial degrees of freedom is required. This allows for space/slow time processing to be applied to mitigate the ground clutter. However, multichannel SAR (M-SAR) systems are very expensive and the requirements in terms of baseline length can be very restrictive. In this study a processing scheme that exploits high PRF single channel SAR system to emulate a multichannel SAR is presented. The signal model for both target and clutter components are presented and the difference with respect to an actual M-SAR are highlighted. The effectiveness of the proposed processing is then demonstrated on simulated a measured dataset

Are Adolescent Risk Assessment Tools Sensitive to Change? A Framework and Examination of the SAVRY and the YLS/CMI

Although many adolescent risk assessment tools include an emphasis on dynamic factors, little research has examined the extent to which these tools are capable of measuring change. In this article, we outline a framework to evaluate a tool’s capacity to measure change. This framework includes: (1) measurement error and reliable change, and (2) sensitivity (i.e., internal, external, and relative sensitivity). We then used this framework to evaluate the Structured Assessment of Violence Risk in Youth (SAVRY) and Youth Level of Service/Case Management Inventory (YLS/CMI). Research assistants conducted 509 risk assessments with 146 adolescents on probation (101 male, 45 female), who were assessed every 3 months over a 1-year period. Internal sensitivity was partially supported, as a modest proportion of youth showed changes over time. External sensitivity (i.e., the association between change scores and reoffending) was also partially supported. In particular, 22% of the associations between change scores and any and violent reoffending were significant at a 6-month follow-up. However, only one change score (i.e., Peer Associations) remained significant after the Bonferroni correction was applied. Finally, relative sensitivity was not supported, as the SAVRY and YLS/CMI was not more dynamic than the Psychopathy Checklist: Youth Version (PCL:YV). Specifically, the 1-year rank-order stability coefficients for the SAVRY, YLS/CMI, and PCL:YV Total Scores were .78, .75, and .76, respectively. Although the SAVRY and YLS/CMI hold promise, further efforts may help to enhance sensitivity to short-term changes in risk

Does Reassessment of Risk Improve Predictions? A Framework and Examination of the SAVRY and YLS/CMI

Although experts recommend regularly reassessing adolescents\u27 risk for violence, it is unclear whether reassessment improves predictions. Thus, in this prospective study, we tested three hypotheses as to why reassessment might improve predictions, namely the shelf-life, dynamic change, and familiarity hypotheses. Research assistants (RAs) rated youth on the Structured Assessment of Violence Risk in Youth (SAVRY) and the Youth Level of Service/Case Management Inventory (YLS/CMI) every three months over a one-year period, conducting 624 risk assessments with 156 youth on probation. We then examined charges for violence and any offence over a two-year follow-up period, and youths\u27 self-reports of reoffending. Contrary to the shelf-life hypothesis, predictions did not decline or expire over time. Instead, time-dependent area under the curve scores remained consistent across the follow-up period. Contrary to the dynamic change hypothesis, changes in youth\u27s risk total scores, compared to what is average for that youth, did not predict changes in reoffending. Finally, contrary to the familiarity hypothesis, reassessments were no more predictive than initial assessments, despite RAs\u27 increased familiarity with youth. Before drawing conclusions, researchers should evaluate the extent to which youth receiving the usual probation services show meaningful short-term changes in risk and if so, whether risk assessment tools are sensitive to these changes

An Evaluation of the Predictive Validity of the SAVRY and YLS/CMI in Justice-Involved Youth with Fetal Alcohol Spectrum Disorder

Despite the high prevalence of fetal alcohol spectrum disorder (FASD) in youth criminal justice settings, there is currently no research supporting the use of violence risk assessment tools in this population. This study examined the predictive validity of total and domain scores on the Structured Assessment of Violence Risk in Youth (SAVRY) and the Youth Level of Service/Case Management Inventory (YLS/CMI) in justice-involved youth with FASD. Participants were 100 justice-involved youth (ages 12 to 23, 81% male), including 50 diagnosed with FASD and 50 without FASD or prenatal alcohol exposure. The SAVRY and YLS/CMI were prospectively coded based on interview and file review, with recidivism (both any and violent specifically) coded one-year post baseline assessment. Results provide preliminary support for the validity of the SAVRY and YLS/CMI in predicting recidivism in justice-involved youth with FASD. Higher ratings across SAVRY and YLS/CMI domains were found in youth with FASD, underscoring a critical need for assessments and interventions to buffer recidivism risk and address clinical needs

Association between active genes occurs at nuclear speckles and is modulated by chromatin environment

Genes on different chromosomes can be spatially associated in the nucleus in several transcriptional and regulatory situations; however, the functional significance of such associations remains unclear. Using human erythropoiesis as a model, we show that five cotranscribed genes, which are found on four different chromosomes, associate with each other at significant but variable frequencies. Those genes most frequently in association lie in decondensed stretches of chromatin. By replacing the mouse α-globin gene cluster in situ with its human counterpart, we demonstrate a direct effect of the regional chromatin environment on the frequency of association, whereas nascent transcription from the human α-globin gene appears unaffected. We see no evidence that cotranscribed erythroid genes associate at shared transcription foci, but we do see stochastic clustering of active genes around common nuclear SC35-enriched speckles (hence the apparent nonrandom association between genes). Thus, association between active genes may result from their location on decondensed chromatin that enables clustering around common nuclear speckles

The Post-Anaesthesia N-acetylcysteine Cognitive Evaluation (PANACEA) trial: study protocol for a randomised controlled trial

BACKGROUND: Some degree of cognitive decline after surgery occurs in as many as one quarter of elderly surgical patients, and this decline is associated with increased morbidity and mortality. Cognition may be affected across a range of domains, including memory, psychomotor skills, and executive function. Whilst the exact mechanisms of cognitive change after surgery are not precisely known, oxidative stress and subsequent neuroinflammation have been implicated. N-acetylcysteine (NAC) acts via multiple interrelated mechanisms to influence oxidative homeostasis, neuronal transmission, and inflammation. NAC has been shown to reduce oxidative stress and inflammation in both human and animal models. There is clinical evidence to suggest that NAC may be beneficial in preventing the cognitive decline associated with both acute physiological insults and dementia-related disorders. To date, no trials have examined perioperative NAC as a potential moderator of postoperative cognitive changes in the noncardiac surgery setting.METHODS AND DESIGN: This is a single-centre, randomised, double-blind, placebo-controlled clinical trial, with a between-group, repeated-measures, longitudinal design. The study will recruit 370 noncardiac surgical patients at the University Hospital Geelong, aged 60 years or older. Participants are randomly assigned to receive either NAC or placebo (1:1 ratio), and groups are stratified by age and surgery type. Participants undergo a series of neuropsychological tests prior to surgery, 7 days, 3 months, and 12 months post surgery. It is hypothesised that the perioperative administration of NAC will reduce the degree of postoperative cognitive changes at early and long-term follow-up, as measured by changes on individual measures of the neurocognitive battery, when compared with placebo. Serum samples are taken on the day of surgery and on day 2 post surgery to quantitate any changes in levels of biomarkers of inflammation and oxidative stress.DISCUSSION: The PANACEA trial aims to examine the potential efficacy of perioperative NAC to reduce the severity of postoperative cognitive dysfunction in an elderly, noncardiac surgery population. This is an entirely novel approach to the prevention of postoperative cognitive dysfunction and will have high impact and translatable outcomes if NAC is found to be beneficial

First Light LBT AO Images of HR 8799 bcde at 1.65 and 3.3 Microns: New Discrepancies between Young Planets and Old Brown Dwarfs

As the only directly imaged multiple planet system, HR 8799 provides a unique opportunity to study the physical properties of several planets in parallel. In this paper, we image all four of the HR 8799 planets at H-band and 3.3 microns with the new LBT adaptive optics system, PISCES, and LBTI/LMIRCam. Our images offer an unprecedented view of the system, allowing us to obtain H and 3.3$ micron photometry of the innermost planet (for the first time) and put strong upper-limits on the presence of a hypothetical fifth companion. We find that all four planets are unexpectedly bright at 3.3 microns compared to the equilibrium chemistry models used for field brown dwarfs, which predict that planets should be faint at 3.3 microns due to CH4 opacity. We attempt to model the planets with thick-cloudy, non-equilibrium chemistry atmospheres, but find that removing CH4 to fit the 3.3 micron photometry increases the predicted L' (3.8 microns) flux enough that it is inconsistent with observations. In an effort to fit the SED of the HR 8799 planets, we construct mixtures of cloudy atmospheres, which are intended to represent planets covered by clouds of varying opacity. In this scenario, regions with low opacity look hot and bright, while regions with high opacity look faint, similar to the patchy cloud structures on Jupiter and L/T transition brown-dwarfs. Our mixed cloud models reproduce all of the available data, but self-consistent models are still necessary to demonstrate their viability.Comment: Accepted to Ap

Rotation of planet-harbouring stars

The rotation rate of a star has important implications for the detectability, characterisation and stability of any planets that may be orbiting it. This chapter gives a brief overview of stellar rotation before describing the methods used to measure the rotation periods of planet host stars, the factors affecting the evolution of a star's rotation rate, stellar age estimates based on rotation, and an overview of the observed trends in the rotation properties of stars with planets.Comment: 16 pages, 4 figures: Invited review to appear in 'Handbook of Exoplanets', Springer Reference Works, edited by Hans J. Deeg and Juan Antonio Belmont

Targeting transcription regulation in cancer with a covalent CDK7 inhibitor

Tumor oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state1, but direct pharmacological inhibition of transcription factors has thus far proven difficult2. However, the transcriptional machinery contains various enzymatic co-factors that can be targeted for development of new therapeutic candidates3, including cyclin-dependent kinases (CDKs)4. Here we present the discovery and characterization of the first covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell line profiling indicates that a subset of cancer cell lines, including T-ALL, exhibit exceptional sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and this transcription factor’s key role in the core transcriptional regulatory circuitry of these tumor cells. Pharmacological modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumor types exhibiting extreme dependencies on transcription for maintenance of the oncogenic state