Suppression of the NF-κB cofactor Bcl3 inhibits mammary epithelial cell apoptosis and, in breast tumours, correlates with poor prognosis

Background Several transcription factors have been shown to play important roles in the regulation of apoptosis at the onset of murine mammary involution. These include LIF-activated STAT3, c/ebpdelta, Ap-1 and IKK/NF-κB-mediated regulation of death receptor ligands. A study of STAT3 and STAT5 transcriptional targets in mammary epithelial cells in vitro showed that both c/ebpdelta and c-fos (a component of Ap-1) were upregulated by STAT3, suggesting a degree of interdependence between these transcription factor pathways in mediating their apoptotic effects. Interestingly, while no NF-κB or IKK genes were significantly regulated by STATs, the NF-κB cofactor gene, Bcl3, was found to be a principal transcriptional target of STAT3. This factor plays a role in altering the transcriptional capacity of specific NF-κB subunits and has previously been described as an oncogene in B-cell lymphomas. In this study we set out to establish whether Bcl3 had a role in regulating the cell fate of mammary epithelial cells either in the normal mammary gland or in mammary/breast cancer. Methods Archived material representing a range of tumour grades and types was collected from breast cancer patients immediately after surgery (tumour tissues = 122, normal tissues = 32). The median follow-up of the patients was 120 months (range 12 to 156 months). QRT-PCR for Bcl3 was performed and this information was used to determine statistically significant correlations with the clinical data on breast pathology. MCF7, T47D and MDA-MB231 human breast cancer cell lines were subjected to Bcl3-specific siRNA knockdown and subsequently assessed for cell motility characteristics using ECIS technology. Bcl3-knockout mice were assessed histologically for alterations in apoptosis rate during the adult pregnancy cycle. Western blots, quantitative PCR and DNA binding assays were used to determine the activity of molecular markers of apoptosis in these animals. Bcl3-deficient animals were crossed with mmtv-neu (c-erbB2) mice to establish the role of Bcl3 in primary (neu-dependent) mammary tumour growth, and magnetic resonance imaging was performed on tumour-bearing animals, to establish metastasis rates in the presence/absence of Bcl3. Results An analysis of 122 human breast cancer tissues showed that Bcl3 gene expression was suppressed in a significant proportion of invasive tumours, which correlated with poor prognosis. This also correlated with a significant decrease in Bcl3 gene expression in human breast cancer cell lines exhibiting increased motility characteristics. The effects of siRNA-mediated knockdown of Bcl3 are ongoing. In the mouse mammary gland, Bcl3 expression was restricted to epithelial cells during the first 24 hours of involution. Bcl3 deficiency resulted in a transient delay in the appearance of apoptotic bodies in the early involuting mammary gland in Bcl3-/- mice, while pSTAT3 levels were unchanged compared with equivalent timepoints in control animals. The activities of initiator/executor caspases of both intrinsic and extrinsic pathways were significantly decreased in Bcl3-/- tissues at this time, which correlated with decreases in the expression of key regulators of intrinsic/extrinsic apoptosis. Results from the ongoing magnetic resonance imaging study of tumour incidence/progression in mmtv-neu/Bcl3-/- mice will be presented. Conclusion These observations suggest that Bcl3 promotes apoptosis in the mammary gland and provides preliminary evidence of cross-talk between STAT3 and NF-κB pathways, both of which have been implicated in breast cancer. Our current data on Bcl3 in primary breast tumours and breast cancer cell lines contrasts with other studies, to suggest that Bcl3 suppresses the metastatic progression of primary breast cancer and has a neutral role in breast cancer incidence or primary tumour growth

Dinosaur tracks from the Kilmaluag Formation (Bathonian, Middle Jurassic) of Score Bay, Isle of Skye, Scotland, UK

Tracks of a juvenile theropod dinosaur with footprint lengths of between 2 and 9 cm as well as adults of the same ichnospecies with footprints of about 15–25 cm in length were found in the Bathonian (Middle Jurassic) Kilmaluag Formation of Score Bay, northwestern Trotternish Peninsula, Isle of Skye, Scotland, UK. Two footprint sizes occur together on the same bedding plane in the central portion of Score Bay, both in situ and on loose blocks. Another horizon containing footprints above this was also identified. The footprints from the lowest horizon were produced in a desiccated silty mud that was covered with sand. A close association of both adults and juveniles with similar travel direction indicated by the footprints may suggest post-hatching care in theropod dinosaurs. Other footprints, produced on a rippled sandy substrate, have been found on the slightly higher bedding plane at this locality. Loose blocks found 130 m to the northeast in the central part of Score Bay have not been correlated with any in situ sediments, but were preserved in a similar manner to those from the higher bedding plane. These tracks represent the youngest dinosaur remains yet found in Scotland

Liquid chromatography high-resolution TOF analysis: investigation of MSE for broad-spectrum drug screening.

BackgroundHigh-resolution mass spectrometry (HRMS) has the potential to supplement other drug screening platforms used in toxicology laboratories. HRMS offers high analytical specificity, which can be further enhanced by incorporating a fragment ion for each analyte. The ability to obtain precursor ions and fragment ions using elevated collision energies (MS(E)) can help improve the specificity of HRMS methods.MethodsWe developed a broad-spectrum screening method on an ultraperformance liquid chromatography TOF mass spectrometer (UPLC-TOF-MS) using the MS(E) mode. A diverse set of patient samples were subjected to a simple dilute, hydrolyze, and shoot protocol and analyzed in a blind manner. Data were processed with 3 sets of criteria with increasing stringency, and the results were compared with the reference laboratory results.ResultsA combination of retention time match (±0.2 min), a protonated analyte, and fragment ion mass accuracy of ±5 ppm produced zero false-positive results. Using these criteria, we confirmed 92% (253/275) of true positives. The positive confirmation rate increased to 98% (270/275) when the requirement for a fragment ion was dropped, but also produced 53 false positives. A total of 136 additional positive drug findings not identified by the reference methods were identified with the UPLC-TOF-MS.ConclusionsMS(E) provides a unique way to incorporate fragment ion information without the need of precursor ion selection. A primary limitation of requiring a fragment ion for positive identification was that certain drug classes required high-energy collisions, which formed many fragment ions of low abundance that were not readily detected

Effect of home telemonitoring on glycemic and blood pressure control in primary care clinic patients with diabetes

Objective: Patient self-management support may be augmented by using home-based technologies that generate data points that providers can potentially use to make more timely changes in the patients' care. The purpose of this study was to evaluate the effectiveness of short-term targeted use of remote data transmission on treatment outcomes in patients with diabetes who had either out-of-range hemoglobin A1c (A1c) and/or blood pressure (BP) measurements. Materials and Methods: A single-center randomized controlled clinical trial design compared in-home monitoring (n=55) and usual care (n=53) in patients with type 2 diabetes and hypertension being treated in primary care clinics. Primary outcomes were A1c and systolic BP after a 12-week intervention. Results: There were no significant differences between the intervention and control groups on either A1c or systolic BP following the intervention. Conclusions: The addition of technology alone is unlikely to lead to improvements in outcomes. Practices need to be selective in their use of telemonitoring with patients, limiting it to patients who have motivation or a significant change in care, such as starting insulin. Attention to the need for effective and responsive clinic processes to optimize the use of the additional data is also important when implementing these types of technology

The relationship between pre-construction decision-making and the quality of risk control: Testing the time-safety influence curve

Purpose - The purpose of this paper is to explore the relationship between the timing with which decisions are made about how to control work health and safety (WHS) risks in construction project (i.e. either pre- or post-construction) and the quality of risk control outcomes. Design/methodology/approach - Data were collected from 23 construction projects in Australia and the USA. Totally, 43 features of work were identified for analysis and decision making in relation to these features of work was mapped across the life of the projects. The quality of risk control outcomes was assessed using a classification system based on the "hierarchy of control". Within this hierarchy, technological forms of control are preferable to behavioural forms of controls. Findings - The results indicate that risk control outcomes were significantly better in the Australian compared with the US cases. The results also reveal a significant relationship between the quality of risk controls and the timing of risk control selection decisions. The greater the proportion of risk controls selected during the pre-construction stages of a project, the better the risk control outcomes. Research limitations/implications - The results provide preliminary evidence that technological risk controls are more likely to be implemented if WHS risks are considered and controls are selected in the planning and design stages of construction projects. Practical implications - The research highlights the need for WHS risk to be integrated into decision making early in the life of construction projects. Originality/value - Previous research has linked accidents to design. However, the retrospective nature of these studies has not permitted an analysis of the effectiveness of integrating WHS into pre-construction decision making. Prospective studies have been lacking. This research provides empirical evidence in support of the relationship between early consideration of WHS and risk control effectiveness

Self‐reported sleep quality is more closely associated with mental and physical health than chronotype and sleep duration in young adults: A multi‐instrument analysis

Sleep and circadian rhythms are considered to be important determinants of mental and physical health. Epidemiological studies have established the contribution of self‐reported sleep duration, sleep quality and chronotype to health outcomes. Mental health and sleep problems are more common in women and men are more likely to be evening types. Few studies have compared the relative strength of these contributions and few studies have assessed these contributions separately in men and women. Furthermore, sleep and circadian characteristics are typically assessed with a limited number of instruments and a narrow range of variables is considered, leaving the understanding of the relative contribution of different predictors somewhat fractionary. We compared sleep quality, sleep duration and chronotype as predictors for self‐reported mental and physical health and psychological characteristics in 410 men and 261 women aged 18 to 30. To ascertain that results were not dependent on the use of specific instruments we used a multitude of validated instruments including the Morningness‐Eveningness‐Questionnaire, Munich‐ChronoType‐Questionnaire, Pittsburgh‐Sleep‐Quality‐Index, British‐Sleep‐Survey, Karolinska‐Sleep‐Diary, Insomnia‐Severity‐Index, SF‐36‐Health Survey, General‐Health‐Questionnaire, Dutch‐Eating‐Behaviour‐Questionnaire, Big‐Five‐Inventory, Behaviour‐Inhibition‐System‐Behaviour‐Activation‐System, and the Positive‐Affect‐Negative‐Affect‐Schedule. Relative contributions of predictors were quantified as local effect sizes derived from multiple regression models. Across all questionnaires, sleep quality was the strongest independent predictor of health and in particular mental health and more so in women than in men. The effect of sleep duration and social jetlag was inconspicuous. A greater insight into the independent contributions of sleep quality and chronotype may aid the understanding of sleep‐health interactions in women and men

Territorial Tactics: The Socio-spatial Significance of Private Policing Strategies in Cape Town

This paper analyses the policing strategies of private security companies operating in urban space. An existing literature has considered the variety of ways that territory becomes of fundamental importance in the work of public police forces. However, this paper examines territory in the context of private security companies. Drawing on empirical research in Cape Town, it examines how demarcated territories become key subjects in private policing. Private security companies are responsible for a relatively small section of the city, while in contrast the public police ultimately have to see city space as a whole. Hence, private policing strategy becomes one of displacement, especially of so-called undesirables yielding a patchworked public space associated with private enclaves of consumption. The conclusions signal the historical resonances and comparative implications of these political-legal-security dynamics. © 2013 Urban Studies Journal Limited