Expression of the RNA helicase DDX3 and the hypoxia response in breast cancer

<p>Aims: DDX3 is an RNA helicase that has antiapoptotic properties, and promotes proliferation and transformation. In addition, DDX3 was shown to be a direct downstream target of HIF-1α (the master regulatory of the hypoxia response) in breast cancer cell lines. However, the relation between DDX3 and hypoxia has not been addressed in human tumors. In this paper, we studied the relation between DDX3 and the hypoxic responsive proteins in human breast cancer.</p> <p>Methods and Results: DDX3 expression was investigated by immunohistochemistry in breast cancer in comparison with hypoxia related proteins HIF-1α, GLUT1, CAIX, EGFR, HER2, Akt1, FOXO4, p53, ERα, COMMD1, FER kinase, PIN1, E-cadherin, p21, p27, Transferrin receptor, FOXO3A, c-Met and Notch1. DDX3 was overexpressed in 127 of 366 breast cancer patients, and was correlated with overexpression of HIF-1α and its downstream genes CAIX and GLUT1. Moreover, DDX3 expression correlated with hypoxia-related proteins EGFR, HER2, FOXO4, ERα and c-Met in a HIF-1α dependent fashion, and with COMMD1, FER kinase, Akt1, E-cadherin, TfR and FOXO3A independent of HIF-1α.</p> <p>Conclusions: In invasive breast cancer, expression of DDX3 was correlated with overexpression of HIF-1α and many other hypoxia related proteins, pointing to a distinct role for DDX3 under hypoxic conditions and supporting the oncogenic role of DDX3 which could have clinical implication for current development of DDX3 inhibitors.</p&gt

Impact of the Specific Mutation in KRAS Codon 12 Mutated Tumors on Treatment Efficacy in Patients with Metastatic Colorectal Cancer Receiving Cetuximab-Based First-Line Therapy: A Pooled Analysis of Three Trials

Purpose: This study investigated the impact of specific mutations in codon 12 of the Kirsten-ras (KRAS) gene on treatment efficacy in patients with metastatic colorectal cancer (mCRC). Patients: Overall, 119 patients bearing a KRAS mutation in codon 12 were evaluated. All patients received cetuximab-based first-line chemotherapy within the Central European Cooperative Oncology Group (CECOG), AIO KRK-0104 or AIO KRK-0306 trials. Results: Patients with KRAS codon 12 mutant mCRC showed a broad range of outcome when treated with cetuximab-based first-line regimens. Patients with tumors bearing a KRAS p.G12D mutation showed a strong trend to a more favorable outcome compared to other mutations (overall survival 23.3 vs. 14-18 months; hazard ratio 0.66, range 0.43-1.03). An interaction model illustrated that KRAS p.G12C was associated with unfavorable outcome when treated with oxaliplatin plus cetuximab. Conclusion: The present analysis suggests that KRAS codon 12 mutation may not represent a homogeneous entity in mCRC when treated with cetuximab-based first-line therapy. Copyright (C) 2012 S. Karger AG, Base

Self-Assembly of Atomically Thin Chiral Copper Heterostructures Templated by Black Phosphorus

The fabrication of 2D systems for electronic devices is not straightforward, with top‐down low‐yield methods often employed leading to irregular nanostructures and lower quality devices. Here, a simple and reproducible method to trigger self‐assembly of arrays of high aspect‐ratio chiral copper heterostructures templated by the structural anisotropy in black phosphorus (BP) nanosheets is presented. Using quantitative atomic resolution aberration‐corrected scanning transmission electron microscopy imaging, in situ heating transmission electron microscopy and electron energy‐loss spectroscopy arrays of heterostructures forming at speeds exceeding 100 nm s−1 and displaying long‐range order over micrometers are observed. The controlled instigation of the self‐assembly of the Cu heterostructures embedded in BP is achieved using conventional electron beam lithography combined with site specific placement of Cu nanoparticles. Density functional theory calculations are used to investigate the atomic structure and suggest a metallic nature of the Cu heterostructures grown in BP. The findings of this new hybrid material with unique dimensionality, chirality, and metallic nature and its triggered self‐assembly open new and exciting opportunities for next generation, self‐assembling devices

Towards a biological definition of ARDS: are treatable traits the solution?

The pathophysiology of acute respiratory distress syndrome (ARDS) includes the accumulation of protein-rich pulmonary edema in the air spaces and interstitial areas of the lung, variable degrees of epithelial injury, variable degrees of endothelial barrier disruption, transmigration of leukocytes, alongside impaired fluid and ion clearance. These pathophysiological features are different between patients contributing to substantial biological heterogeneity. In this context, it is perhaps unsurprising that a wide range of pharmacological interventions targeting these pathophysiological processes have failed to improve patient outcomes. In this manuscript, our goal is to provide a narrative summary of the potential methods to capture the underlying biological heterogeneity of ARDS and discuss how this information could inform future ARDS redefinitions. We discuss what biological tests are available to identify patients with any of the following predominant biological patterns: (1) epithelial and/or endothelial injury, (2) protein rich pulmonary edema and (3) systemic or within lung inflammatory responses

Stereotyping of medical disability claimants' communication behaviour by physicians: towards more focused education for social insurance physicians

Background: Physicians who hold medical disability assessment interviews (social insurance physicians) are probably influenced by stereotypes of claimants, especially because they have limited time available and they have to make complicated decisions. Because little is known about the influences of stereotyping on assessment interviews, the objectives of this paper were to qualitatively investigate: (1) the content of stereotypes used to classify claimants with regard to the way in which they communicate; (2) the origins of such stereotypes; (3) the advantages and disadvantages of stereotyping in assessment interviews; and (4) how social insurance physicians minimise the undesirable influences of negative stereotyping. Methods: Data were collected during three focus group meetings with social insurance physicians who hold medical disability assessment interviews with sick-listed employees (i.e. claimants). The participants also completed a questionnaire about demographic characteristics. The data were qualitatively analysed in Atlas.ti in four steps, according to the grounded theory and the principle of constant comparison. Results: A total of 22 social insurance physicians participated. Based on their responses, a claimant's communication was classified with regard to the degree of respect and acceptance in the physician-claimant relationship, and the degree of dominance. Most of the social insurance physicians reported that they classify claimants in general groups, and use these classifications to adapt their own communication behaviour. Moreover, the social insurance physicians revealed that their stereotypes originate from information in the claimants' files and first impressions. The main advantages of stereotyping were that this provides a framework for the assessment interview, it can save time, and it is interesting to check whether the stereotype is correct. Disadvantages of stereotyping were that the stereotypes often prove incorrect, they do not give the complete picture, and the claimant's behaviour changes constantly. Social insurance physicians try to minimise the undesirable influences of stereotypes by being aware of counter transference, making formal assessments, staying neutral to the best of their ability, and being compassionate. Conclusions: We concluded that social insurance physicians adapt their communication style to the degree of respect and dominance of claimants in the physician-claimant relationship, but they try to minimise the undesirable influences of stereotypes in assessment interviews. It is recommended that this issue should be addressed in communication skills trainin

Divided attention selectively impairs memory for self-relevant information

Information that is relevant to oneself tends to be remembered more than information that relates to other people, but the role of attention in eliciting this "self-reference effect" is unclear. In the present study, we assessed the importance of attention in self-referential encoding using an ownership paradigm, which required participants to encode items under conditions of imagined ownership by themselves or by another person. Previous work has established that this paradigm elicits a robust self-reference effect, with more "self-owned" items being remembered than "other-owned" items. Access to attentional resources was manipulated using divided-attention tasks at encoding. A significant self-reference effect emerged under full-attention conditions and was related to an increase in episodic recollection for self-owned items, but dividing attention eliminated this memory advantage. These findings are discussed in relation to the nature of self-referential cognition and the importance of attentional resources at encoding in the manifestation of the self-reference effect in memory

Intramyocardial hemorrhage and microvascular obstruction after primary percutaneous coronary intervention

Reperfusion may cause intramyocardial hemorrhage (IMH) by extravasation of erythrocytes through severely damaged endothelial walls. The purpose of the study was to evaluate the clinical significance of IMH in relation to infarct size, microvascular obstruction (MVO) and function in patients after primary percutaneous intervention. Forty-five patients underwent cardiovascular MR imaging (CMR) 1 week and 4 months after primary stenting for a first acute myocardial infarction. T2-weighted spin-echo imaging (T2W) was used to assess infarct related edema and IMH, and delayed enhancement (DE) was used to assess infarct size and MVO. Cine CMR was used to assess left ventricular volumes and function at baseline and at 4 months follow-up. In 22 (49%) patients, IMH was detected as areas of attenuated signal in the core of the high signal intensity region on T2W images. Patients with IMH had larger infarcts, higher left ventricular volumes and lower ejection fraction. Contrast-to-noise ratio (CNR) between hyperintense periphery and the hypo-intense core of the T2W ischemic area correlated to peak CKMB, total infarct size and MVO size. Using univariable analysis, CNR predicted ejection fraction at baseline (β = −0.62, P = 0.003) and follow-up (β = −0.84, P < 0.001). However, after multivariable analysis, baseline ejection fraction and presence of MVO were the only parameters that predicted functional changes at follow-up. IMH was found in the majority of patients with MVO after reperfused myocardial infarction. It was closely related to markers of infarct size, MVO and function, but did not have prognostic significance beyond MVO