Quaking and miR-155 interactions in inflammation and leukemogenesis

Quaking (QKI) is a tumor-suppressor gene encoding a conserved RNA-binding protein, whose expression is downregulated in several solid tumors. Here we report that QKI plays an important role in the immune response and suppression of leukemogenesis. We show that the expression of Qki is reduced in lipopolysaccharide (LPS)-challenged macrophages, suggesting that Qki is a key regulator of LPS signaling pathway. Furthermore, LPS-induced downregulation of Qki expression is miR-155-dependent. Qki overexpression impairs LPS-induced phosphorylation of JNK and particularly p38 MAPKs, in addition to increasing the production of anti-inflammatory cytokine IL-10. In contrast, Qki ablation decreases Fas expression and the rate of Caspase3/7 activity, while increasing the levels of IL-1α, IL-1β and IL-6, and p38 phosphorylation. Similarly, the p38 pathway is also a target of QKI activity in chronic lymphocytic leukemia (CLL)-derived MEC2 cells. Finally, B-CLL patients show lower levels of QKI expression compared with B cells from healthy donor, and Qki is similarily downregulated with the progression of leukemia in Eμ-miR-155 transgenic mice. Altogether, these data implicate QKI in the pathophysiology of inflammation and oncogenesis where miR-155 is involved.     

Pathological Controversies in Breast Cancer: Classification of Ductal Carcinoma In Situ,Sentinel Lymph Nodes and Low Volume Metastatic Disease and Reporting of Neoadjuvant Chemotherapy Specimens

The pathological classification of breast cancer is constantly being updated to reflect the advances in our clinical and biological understanding of the disease. This overview examines new insights into the classification and molecular biology of ductal carcinoma in situ, the pathological handling of sentinel lymph node biopsies and the identification of low volume disease (micrometastases and isolated tumour cells) and the handling and reporting of specimens after neoadjuvant therapy. The molecular subtypes of invasive breast cancer are also represented in ductal carcinoma in situ. It is hoped that alongside traditional histological features, such as cytological grade and the presence of necrosis, this will lead to better classification systems with improved prediction of clinical behaviour, in particular the risk of progression to invasive cancer, and enable more targeted management. Sentinel lymph node biopsy is now the standard of care for early stage breast cancer in clinically node-negative patients. However, the handling and reporting of these specimens remains controversial, largely related to the uncertainties regarding the clinical significance of micrometastases and isolated tumour cells. The increasing use of neoadjuvant therapies has introduced challenges for the pathologist in the handling and interpretation of these specimens. Grading the tumour response, particularly the identification of a complete pathological response, is prognostically important. However, there is still marked variability in reporting these specimens in routine practice, and consensus guidelines for the histopathology reporting of breast cancers after neoadjuvant chemotherapy based on robust, validated evidence are presently lacking.     

Evidence-based health promotion for older people and instrumentalisation: comparing the influence of policy contexts in Austria and England

Health promotion (HP) amongst older people is an increasingly prominent policy concern for governments. The development of an evidence-base and the advocacy of effective interventions in the light of this act as legitimation tools for the overall HP phenomenon – assisting the growth of state and non-state funding for public health initiatives for older people. In structuring decision-making as to which individual projects/initiatives receive funding, frameworks for acknowledging efficacy impact on formats of HP work both positively and negatively. Drawing on recent research across the EU and focusing on the specific national contexts of Austria and England, this comparative policy analysis triangulates best-practice modelling, evaluation data and interviews with project coordinators to explore how policy contexts impact on the nature and format of HP interventions. Amidst a developing awareness of what effective practice looks like, successful HP initiatives must advocate their legitimacy within narrow rules of quality, where measurable outcomes have become the keys which unlock financial resources. Findings across both countries suggest that this instrumentalisation of legitimation, driven by economic pressures and bureaucratic generalisability, threatens the rationality of HP. From a Habermasian perspective, tensions emerge between projects’ remaining reflexive towards processes and their need to articulate the ‘success’ of the interventions in a language of outcomes. Over time, in an era where resources are increasingly scarce and competition over these intensifies, a danger exists whereby the instrumentality of HP begins to separate from, and impinge upon, the capacity for projects to think and act holistically.