A role for eukaryotic initiation factor 4B overexpression in the pathogenesis of diffuse large B-cell lymphoma.

Dysregulated expression of factors that control protein synthesis is associated with poor prognosis of many cancers, but the underlying mechanisms are not well defined. Analysis of the diffuse large B-cell lymphoma (DLBCL) translatome revealed selective upregulation of mRNAs encoding anti-apoptotic and DNA repair proteins. We show that enhanced synthesis of these proteins in DLBCL is mediated by the relief of repression that is normally imposed by structure in the 5'-untranslated regions of their corresponding mRNAs. This process is driven by signaling through mammalian target of rapamycin, resulting in increased synthesis of eukaryotic initiation factor (eIF) 4B complex (eIF4B), a known activator of the RNA helicase eIF4A. Reducing eIF4B expression alone is sufficient to decrease synthesis of proteins associated with enhanced tumor cell survival, namely DAXX, BCL2 and ERCC5. Importantly, eIF4B-driven expression of these key survival proteins is directly correlated with patient outcome, and eIF4B, DAXX and ERCC5 are identified as novel prognostic markers for poor survival in DLBCL. Our work provides new insights into the mechanisms by which the cancer-promoting translational machinery drives lymphomagenesis

Fast fluorescence microscopy for imaging the dynamics of embryonic development

Live imaging has gained a pivotal role in developmental biology since it increasingly allows real-time observation of cell behavior in intact organisms. Microscopes that can capture the dynamics of ever-faster biological events, fluorescent markers optimal for in vivo imaging, and, finally, adapted reconstruction and analysis programs to complete data flow all contribute to this success. Focusing on temporal resolution, we discuss how fast imaging can be achieved with minimal prejudice to spatial resolution, photon count, or to reliably and automatically analyze images. In particular, we show how integrated approaches to imaging that combine bright fluorescent probes, fast microscopes, and custom post-processing techniques can address the kinetics of biological systems at multiple scales. Finally, we discuss remaining challenges and opportunities for further advances in this field

Intrinsic bias in breast cancer gene expression data sets

<p>Abstract</p> <p>Background</p> <p>While global breast cancer gene expression data sets have considerable commonality in terms of their data content, the populations that they represent and the data collection methods utilized can be quite disparate. We sought to assess the extent and consequence of these systematic differences with respect to identifying clinically significant prognostic groups.</p> <p>Methods</p> <p>We ascertained how effectively unsupervised clustering employing randomly generated sets of genes could segregate tumors into prognostic groups using four well-characterized breast cancer data sets.</p> <p>Results</p> <p>Using a common set of 5,000 randomly generated lists (70 genes/list), the percentages of clusters with significant differences in metastasis latencies (HR p-value < 0.01) was 62%, 15%, 21% and 0% in the NKI2 (Netherlands Cancer Institute), Wang, TRANSBIG and KJX64/KJ125 data sets, respectively. Among ER positive tumors, the percentages were 38%, 11%, 4% and 0%, respectively. Few random lists were predictive among ER negative tumors in any data set. Clustering was associated with ER status and, after globally adjusting for the effects of ER-α gene expression, the percentages were 25%, 33%, 1% and 0%, respectively. The impact of adjusting for ER status depended on the extent of confounding between ER-α gene expression and markers of proliferation.</p> <p>Conclusion</p> <p>It is highly probable to identify a statistically significant association between a given gene list and prognosis in the NKI2 dataset due to its large sample size and the interrelationship between ER-α expression and markers of proliferation. In most respects, the TRANSBIG data set generated similar outcomes as the NKI2 data set, although its smaller sample size led to fewer statistically significant results.</p

Practicing physiotherapy in Danish private practice: an ethical perspective.

Despite an increasingly growth of professional guidelines, textbooks and research about ethics in health care, awareness about ethics in Danish physiotherapy private practice seen vague. This article explores how physiotherapists in Danish private practice, from an ethical perspective, perceive to practice physiotherapy. The empirical data consists of interviews with twenty-one physiotherapists. The interviews are analysed from a hermeneutic approach, inspired by Ricoeur's textual interpretation of distanciation. The analysis follows three phases: naïve reading, structural analysis and comprehensive analysis. Four main themes are constructed: Beneficence as the driving force; Disciplining the patient through the course of physiotherapy; Balancing between being a trustworthy professional and a businessperson; The dream of a code of practice. Private practice physiotherapy is embedded in a structural frame directed by both political and economical conditions that shape the conditions for practicing physiotherapy. It means that beneficence in practice is a balance between the patient, the physiotherapists themselves and the business. Beneficence towards the patient is expressed as an implicit demand. Physiotherapeutic practice is expressed as being an integration of professionalism and personality which implies that the physiotherapists also have to benefit themselves. Private practice seems to be driven by a paternalistic approach towards the patient, where disciplining the patient is a crucial element of practice, in order to optimise profit. Physiotherapists wish for a more beneficent practice in the future by aiming at bridging 'to be' and 'ought to be'

Influenza vaccination of healthcare workers in acute-care hospitals: a case-control study of its effect on hospital-acquired influenza among patients

<p>Abstract</p> <p>Background</p> <p>In acute-care hospitals, no evidence of a protective effect of healthcare worker (HCW) vaccination on hospital-acquired influenza (HAI) in patients has been documented. Our study objective was to ascertain the effectiveness of influenza vaccination of HCW on HAI among patients.</p> <p>Methods</p> <p>A nested case-control investigation was implemented in a prospective surveillance study of influenza-like illness (ILI) in a tertiary acute-care university hospital. Cases were patients with virologically-confirmed influenza occurring ≥ 72 h after admission, and controls were patients with ILI presenting during hospitalisation with negative influenza results after nasal swab testing. Four controls per case, matched per influenza season (2004-05, 2005-06 and 2006-07), were randomly selected. Univariate and multivariate conditional logistic regression models were fitted to assess factors associated with HAI among patients.</p> <p>Results</p> <p>In total, among 55 patients analysed, 11 (20%) had laboratory-confirmed HAI. The median HCW vaccination rate in the units was 36%. The median proportion of vaccinated HCW in these units was 11.5% for cases vs. 36.1% for the controls (<it>P </it>= 0.11); 2 (20%) cases and 21 (48%) controls were vaccinated against influenza in the current season (<it>P </it>= 0.16). The proportion of ≥ 35% vaccinated HCW in short-stay units appeared to protect against HAI among patients (odds ratio = 0.07; 95% confidence interval 0.005-0.98), independently of patient age, influenza season and potential influenza source in the units.</p> <p>Conclusions</p> <p>Our observational study indicates a shielding effect of more than 35% of vaccinated HCW on HAI among patients in acute-care units. Investigations, such as controlled clinical trials, are needed to validate the benefits of HCW vaccination on HAI incidence in patients.</p

Use of horseradish peroxidase for gene-directed enzyme prodrug therapy with paracetamol

Gene therapy is a potential method of treating cancer with a greater degree of targeting than conventional therapies. In addition, therapy can be directed towards cells within the tumour population that are traditionally resistant to current treatment schedules. Horseradish peroxidase (HRP) can oxidise paracetamol to N-acetyl-p-benzoquinoneimine via a one-electron pathway. Incubation of human cells expressing HRP with 0.5–10 mm paracetamol reduced clonogenic survival, but had little effect on control cells. A small increase in apoptosis was seen and a decrease in the number of cells undergoing mitosis, consistent with reports in hepatocytes using higher paracetamol concentrations. The cytotoxicity was also seen under conditions of severe hypoxia (catalyst induced anoxia), indicating that the HRP/paracetamol combination may be suitable for hypoxia-targeted gene therapy

The General Age of Leadership: Older-Looking Presidential Candidates Win Elections during War

As nation-state leaders age they increasingly engage in inter-state militarized disputes yet in industrialized societies a steady decrease in testosterone associated with aging is observed – which suggests a decrease in dominance behavior. The current paper points out that from modern societies to Old World monkeys increasing both in age and social status encourages dominant strategies to maintain acquired rank. Moreover, it is argued this consistency has shaped an implicit prototype causing followers to associate older age with dominance leadership. It is shown that (i) faces of older leaders are preferred during intergroup conflict and (ii) morphing U.S. Presidential candidates to appear older or younger has an overriding effect on actual election outcomes. This indicates that democratic voting can be systematically adjusted by activating innate biases. These findings appear to create a new line of research regarding the biology of leadership and contextual cues of age

Lunar exploration: opening a window into the history and evolution of the inner Solar System

The lunar geological record contains a rich archive of the history of the inner Solar System, including information relevant to understanding the origin and evolution of the Earth-Moon system, the geological evolution of rocky planets, and our local cosmic environment. This paper provides a brief review of lunar exploration to-date, and describes how future exploration initiatives will further advance our understanding of the origin and evolution of the Moon, the Earth-Moon system, and of the Solar System more generally. It is concluded that further advances will require the placing of new scientific instruments on, and the return of additional samples from, the lunar surface. Some of these scientific objectives can be achieved robotically, for example by in situ geochemical and geophysical measurements and through carefully targeted sample return missions. However, in the longer term, we argue that lunar science would greatly benefit from renewed human operations on the surface of the Moon, such as would be facilitated by implementing the recently proposed Global Exploration Roadmap