Evaluation of the current knowledge limitations in breast cancer research: a gap analysis

BACKGROUND A gap analysis was conducted to determine which areas of breast cancer research, if targeted by researchers and funding bodies, could produce the greatest impact on patients. METHODS Fifty-six Breast Cancer Campaign grant holders and prominent UK breast cancer researchers participated in a gap analysis of current breast cancer research. Before, during and following the meeting, groups in seven key research areas participated in cycles of presentation, literature review and discussion. Summary papers were prepared by each group and collated into this position paper highlighting the research gaps, with recommendations for action. RESULTS Gaps were identified in all seven themes. General barriers to progress were lack of financial and practical resources, and poor collaboration between disciplines. Critical gaps in each theme included: (1) genetics (knowledge of genetic changes, their effects and interactions); (2) initiation of breast cancer (how developmental signalling pathways cause ductal elongation and branching at the cellular level and influence stem cell dynamics, and how their disruption initiates tumour formation); (3) progression of breast cancer (deciphering the intracellular and extracellular regulators of early progression, tumour growth, angiogenesis and metastasis); (4) therapies and targets (understanding who develops advanced disease); (5) disease markers (incorporating intelligent trial design into all studies to ensure new treatments are tested in patient groups stratified using biomarkers); (6) prevention (strategies to prevent oestrogen-receptor negative tumours and the long-term effects of chemoprevention for oestrogen-receptor positive tumours); (7) psychosocial aspects of cancer (the use of appropriate psychosocial interventions, and the personal impact of all stages of the disease among patients from a range of ethnic and demographic backgrounds). CONCLUSION Through recommendations to address these gaps with future research, the long-term benefits to patients will include: better estimation of risk in families with breast cancer and strategies to reduce risk; better prediction of drug response and patient prognosis; improved tailoring of treatments to patient subgroups and development of new therapeutic approaches; earlier initiation of treatment; more effective use of resources for screening populations; and an enhanced experience for people with or at risk of breast cancer and their families. The challenge to funding bodies and researchers in all disciplines is to focus on these gaps and to drive advances in knowledge into improvements in patient care

Regulation of Progranulin Expression in Human Microglia and Proteolysis of Progranulin by Matrix Metalloproteinase-12 (MMP-12)

Background: The essential role of progranulin (PGRN) as a neurotrophic factor has been demonstrated by the discovery that haploinsufficiency due to GRN gene mutations causes frontotemporal lobar dementia. In addition to neurons, microglia in vivo express PGRN, but little is known about the regulation of PGRN expression by microglia. Goal: In the current study, we examined the regulation of expression and function of PGRN, its proteolytic enzyme macrophage elastase (MMP-12), as well as the inhibitor of PGRN proteolysis, secretory leukocyte protease inhibitor (SLPI), in human CNS cells. Methods: Cultures of primary human microglia and astrocytes were stimulated with the TLR ligands (LPS or poly IC), Th1 cytokines (IL-1/IFNc), or Th2 cytokines (IL-4, IL-13). Results were analyzed by Q-PCR, immunoblotting or ELISA. The roles of MMP-12 and SLPI in PGRN cleavage were also examined. Results: Unstimulated microglia produced nanogram levels of PGRN, and PGRN release from microglia was suppressed by the TLR ligands or IL-1/IFNc, but increased by IL-4 or IL-13. Unexpectedly, while astrocytes stimulated with proinflammatory factors released large amounts of SLPI, none were detected in microglial cultures. We also identified MMP-12 as a PGRN proteolytic enzyme, and SLPI as an inhibitor of MMP-12-induced PGRN proteolysis. Experiments employing PGRN siRNA demonstrated that microglial PGRN was involved in the cytokine and chemokine production following TLR3/4 activation

The Numbers Behind Mushroom Biodiversity

Fungi are among the most diverse groups of organisms on Earth. with a global diversity estimated at 0.8 million to 5.1 million species. They play fundamental ecological roles as decomposers, mutualists, and pathogens, growing in almost all habitats and being important as sources of food and health benefits, income, and to maintain forest health. Global assessment of wild edible fungi indicate the existence of 2327 useful wild species; 2166 edible and 1069 used as food; 470 medicinal species. Several million tonnes are collected, consumed, and sold each year in over 80 countries. The major mushroom-producing countries in 2012 were China, Italy, USA, and The Netherlands, with 80% of the world production, 64% of which came from China. The European Union produces 24% of the world production. Italy is the largest European producer, Poland is the largest exporter, UK the largest importer.Fungi are difficult to preserve and fossilize and due to the poor preservation of most fungal structures, it has been difficult to interpret the fossil record of fungi. Hyphae, the vegetative bodies of fungi, bear few distinctive morphological characteristicss, and organisms as diverse as cyanobacteria, eukaryotic algal groups, and oomycetes can easily be mistaken for them (Taylor & Taylor 1993). Fossils provide minimum ages for divergences and genetic lineages can be much older than even the oldest fossil representative found. According to Berbee and Taylor (2010), molecular clocks (conversion of molecular changes into geological time) calibrated by fossils are the only available tools to estimate timing of evolutionary events in fossil‐poor groups, such as fungi. The arbuscular mycorrhizal symbiotic fungi from the division Glomeromycota, generally accepted as the phylogenetic sister clade to the Ascomycota and Basidiomycota, have left the most ancient fossils in the Rhynie Chert of Aberdeenshire in the north of Scotland (400 million years old). The Glomeromycota and several other fungi have been found associated with the preserved tissues of early vascular plants (Taylor et al. 2004a). Fossil spores from these shallow marine sediments from the Ordovician that closely resemble Glomeromycota spores and finely branched hyphae arbuscules within plant cells were clearly preserved in cells of stems of a 400 Ma primitive land plant, Aglaophyton, from Rhynie chert 455–460 Ma in age (Redecker et al. 2000; Remy et al. 1994) and from roots from the Triassic (250–199 Ma) (Berbee & Taylor 2010; Stubblefield et al. 1987).info:eu-repo/semantics/publishedVersio

Mourning and melancholia revisited: correspondences between principles of Freudian metapsychology and empirical findings in neuropsychiatry

Freud began his career as a neurologist studying the anatomy and physiology of the nervous system, but it was his later work in psychology that would secure his place in history. This paper draws attention to consistencies between physiological processes identified by modern clinical research and psychological processes described by Freud, with a special emphasis on his famous paper on depression entitled 'Mourning and melancholia'. Inspired by neuroimaging findings in depression and deep brain stimulation for treatment resistant depression, some preliminary physiological correlates are proposed for a number of key psychoanalytic processes. Specifically, activation of the subgenual cingulate is discussed in relation to repression and the default mode network is discussed in relation to the ego. If these correlates are found to be reliable, this may have implications for the manner in which psychoanalysis is viewed by the wider psychological and psychiatric communities

Secretory Leukocyte Protease Inhibitor inhibits neutrophil apoptosis.

SUMMARY AT A GLANCE: Secretory leukocyte proteinase inhibitor (SLPI) is a major anti-elastase barrier at the epithelial surfaces of upper respiratory tract. Our findings indicate clear up-regulation of SLPI in response to endotoxin in nasal secretions. In addition, SLPI shows dose-dependent anti-apoptotic and chemotactic effects on primary human neutrophils. ABSTRACT: Background and objective: The Secretory Leukocyte Protease Inhibitor (SLPI) is a major anti-elastase barrier at the epithelial surfaces of upper respiratory tract. In addition to its anti-protease activity, SLPI has been shown to express anti-bacterial, anti-viral and anti-inflammatory properties. Methods: We measured SLPI concentration in nasal lavage fluid of healthy volunteers after challenge with endotoxin (LPS) and evaluated SLPI effects in vitro on neutrophil chemotaxis, adhesion, cytokine (IL-8) release and apoptosis. Results: SLPI concentration in nasal lavage (n = 9) 2, 6 and 24 hrs after the challenge with LPS (25 µg) increased from 32% to 238% compared to baseline (226 ± 71 ng/ml). In vitro, SLPI (20 to 80µg/ml) induced neutrophil chemotaxis (6-fold, p < 0.001) and decreased neutrophil apoptosis by 73% (p = 0.006), relative to controls. However, SLPI had no affect on IL-8 release or neutrophil adhesion to fibronectin. SLPI-positive immunoreactivity was co-localised with neutrophils in lung specimens from patients with chronic obstructive pulmonary disease. Conclusions: Our findings indicate up-regulation of SLPI in response to LPS in nasal secretions and show anti-apoptotic effects of SLPI in primary human neutrophils suggesting a new role of SLPI during neutrophilic inflammation