Migration Stimulating Factor (MSF): Its Role in the Tumour Microenvironment.

Migration Stimulating Factor (MSF) is a 70 kDa truncated isoform of fibronectin (FN); its mRNA is generated from the FN gene by an unusual two-stage processing. Unlike full-length FN, MSF is not a matrix molecule but a soluble protein which displays cytokine-like activities not displayed by any other FN isoform due to steric hindrance. There are two isoforms of MSF; these are referred to as MSF+aa and MSF-aa, while the term MSF is used to include both.MSF was first identified as a motogen secreted by foetal and cancer-associated fibroblasts in tissue culture. It is also produced by sprouting (angiogenic) endothelial cells, tumour cells and activated macrophages. Keratinocytes and resting endothelial cells secrete inhibitors of MSF that have been identified as NGAL and IGFBP-7, respectively. MSF+aa and MSF-aa show distinct functionality in that only MSF+aa is inhibited by NGAL.MSF is present in 70-80% of all tumours examined, expressed by the tumour cells as well as by fibroblasts, endothelial cells and macrophages in the tumour microenvironment (TME). High MSF expression is associated with tumour progression and poor prognosis in all tumours examined, including breast carcinomas, non-small cell lung cancer (NSCLC), salivary gland tumours (SGT) and oral squamous cell carcinomas (OSCC). Epithelial and stromal MSF carry independent prognostic value. MSF is also expressed systemically in cancer patients, being detected in serum and produced by fibroblast from distal uninvolved skin. MSF-aa is the main isoform associated with cancer, whereas MSF+aa may be expressed by both normal and malignant tissues.The expression of MSF is not invariant; it may be switched on and off in a reversible manner, which requires precise interactions between soluble factors present in the TME and the extracellular matrix in contact with the cells. MSF expression in fibroblasts may be switched on by a transient exposure to several molecules, including TGFß1 and MSF itself, indicating an auto-inductive capacity.Acting by both paracrine and autocrine mechanisms, MSF stimulates cell migration/invasion, induces angiogenesis and cell differentiation and alters the matrix and cellular composition of the TME. MSF is also a survival factor for sprouting endothelial cells. IGD tri- and tetra-peptides mimic the motogenic and angiogenic activities of MSF, with both molecules inhibiting AKT activity and requiring αvß3 functionality. MSF is active at unprecedently low concentrations in a manner which is target cell specific. Thus, different bioactive motifs and extracellular matrix requirements apply to fibroblasts, endothelial cells and tumour cells. Unlike other motogenic and angiogenic factors, MSF does not affect cell proliferation but it stimulates tumour growth through its angiogenic effect and downstream mechanisms.The epithelial-stromal pattern of expression and range of bioactivities displayed puts MSF in the unique position of potentially promoting tumour progression from both the "seed" and the "soil" perspectives.

Prospective development and validation of a model to predict heart failure hospitalisation.

OBJECTIVE: Acute heart failure syndrome (AHFS) is a major cause of hospitalisation and imparts a substantial burden on patients and healthcare systems. Tools to define risk of AHFS hospitalisation are lacking. METHODS: A prospective cohort study (n=628) of patients with stable chronic heart failure (CHF) secondary to left ventricular systolic dysfunction was used to derive an AHFS prediction model which was then assessed in a prospectively recruited validation cohort (n=462). RESULTS: Within the derivation cohort, 44 (7%) patients were hospitalised as a result of AHFS during 1 year of follow-up. Predictors of AHFS hospitalisation included furosemide equivalent dose, the presence of type 2 diabetes mellitus, AHFS hospitalisation within the previous year and pulmonary congestion on chest radiograph, all assessed at baseline. A multivariable model containing these four variables exhibited good calibration (Hosmer-Lemeshow p=0.38) and discrimination (C-statistic 0.77; 95% CI 0.71 to 0.84). Using a 2.5% risk cut-off for predicted AHFS, the model defined 38.5% of patients as low risk, with negative predictive value of 99.1%; this low risk cohort exhibited <1% excess all-cause mortality per annum when compared with contemporaneous actuarial data. Within the validation cohort, an identically applied model derived comparable performance parameters (C-statistic 0.81 (95% CI 0.74 to 0.87), Hosmer-Lemeshow p=0.15, negative predictive value 100%). CONCLUSIONS: A prospectively derived and validated model using simply obtained clinical data can identify patients with CHF at low risk of hospitalisation due to AHFS in the year following assessment. This may guide the design of future strategies allocating resources to the management of CHF.

Resolving inequalities in care? Reduced mortality in the elderly after acute coronary syndromes. The Myocardial Ischaemia National Audit Project 2003-2010.

AIMS: To examine age-dependent in-hospital mortality for hospitalization with acute coronary syndromes (ACS) in England and Wales. METHODS AND RESULTS: Mixed-effects regression analysis using data from 616 011 ACS events at 255 hospitals as recorded in the Myocardial Ischemia National Audit Project (MINAP) 2003-2010; 102 415 (16.7%) patients were aged <55 years and 72 721 (11.9%) ≥85 years. Patients ≥85 years with ST-elevation myocardial infarction (STEMI) were less likely to receive emergency reperfusion therapy than those <55 years (RR = 0.27, 95% CI: 0.25-0.28). Older patients had greater lengths of stay (P< 0.001) and higher in-hospital mortality (P< 0.001). For STEMI and non-ST-elevation myocardial infarction (NSTEMI), there were reductions in in-hospital mortality from 2003 to 2010 across all age groups including the very elderly. For STEMI ≥ 85 years, in-hospital mortality reduced from 30.1% in 2003 to 19.4% in 2010 (RR = 0.54, 95% CI: 0.38-0.75, P< 0.001), and for NSTEMI ≥ 85 years, from 31.5% in 2003 to 20.4% in 2010 (RR = 0.56, 95% CI: 0.42-0.73, P< 0.001). Findings were upheld after multi-level adjustment (base = 2003): male STEMI 2010 OR = 0.60, 95% CI: 0.48-0.75; female STEMI 2010 OR = 0.55, 95% CI: 0.42-0.71; male NSTEMI OR = 0.50, 95% CI: 0.42-0.60; female NSTEMI OR = 0.49, 95% CI: 0.40-0.59. CONCLUSION: For patients hospitalized with ACS in England and Wales, there have been substantial reductions in in-hospital mortality rates from 2003 to 2010 across all age groups. The temporal improvements in mortality were similar for sex and type of acute myocardial infarction. Age-dependent inequalities in the management of ACS were apparent.

Involvement of brainstem serotonergic interneurons in the development of a vertebrate spinal locomotor circuit.

Brainstem neurons modulate the rhythmic output of spinal locomotor circuitry in adult vertebrates, but how these influences develop is largely unknown. We demonstrate that the ingrowth of serotonergic axons to the spinal cord of Xenopus tadpoles plays a critical role in locomotor burst development by transforming the output of embryonic amphibian swimming circuitry into a more mature and flexible form. Our experiments show that exposure to a monoamine neurotoxin (5,7 dihydroxytryptamine) deletes serotonergic raphespinal projections and prevents the normal maturation of larval swimming. Furthermore, the mature larval rhythm resumes an embryo-like form following either a pharmacological blockade of serotonin receptors or when receptor activation is prevented by acute spinalization.

Descending serotonergic spinal projections and modulation of locomotor rhythmicity in Rana temporaria embryos.

The neuroanatomy of descending spinal projections from serotonergic raphe interneurons in embryos of the amphibian, Rana temporaria, has been examined around the time of hatching by using immunocytochemical techniques. The results illustrate that at this early stage in development the ventrolateral spinal cord is richly innervated by 5HT immunoreactive (5HTi) raphe spinal axons and associated growth cones. Other regions are devoid of processes. In conjunction, the effects of bath applied 5-hydroxytryptamine (5HT, serotonin) and its metabolic precursor, 5-hydroxytryptophan (5HTP) on locomotor activity, was also investigated by monitoring ventral root activity during fictive swimming in immobilized animals. Fictive swimming activity is similarly modulated by both exogenously applied 5HT and enhanced endogenous release of 5HT (using 5HTP). These agents increase the duration and intensity of ventral root burst, decrease cycle frequency, lengthen rostrocaudal phase delays and reduce swimming episode duration. We conclude that by the time of hatching in Rana temporaria a functional endogenous serotonergic system is established in the spinal cord which modulates the output of the central pattern generator for swimming. We compare and contrast these results with homologous descending pathways in other vertebrates, especially in a related amphibian Xenopus laevis at equivalent stages in development.