Clustering based on clinicophysiologic parameters yielded 4 stable and reproducible clusters that associate with different pathobiological pathways.

Chemokines and their receptors are involved in tumourigenicity and clinicopathological significance of chemokines receptor expression in pancreatic adenocarcinoma (PA) is not fully understood. This study was conducted to determine patients' outcome according to the expressions of CXCR4, CXCR7 and HIF-1a after resection of PA. Immunohistochemistry for CXCR4, CXCR7 and HIF-1a expressions as well as cell proliferative index (Ki-67) was conducted in 71 resected (R0) PA and their 48 related lymph nodes (LN) using tissue microarray. CXCR4 and CXCR7 expressions were positively correlated to HIF-1a suggesting a potential role of HIF-1a in CXCR4 and CXCR7 transcription activation. Patients with CXCR4 high tumour expression had shorter OS than those with low expression (median survival: 9.7 vs 43.2 months, P ¼ 0.0006), a higher risk of LN metastases and liver recurrence. In multivariate analysis, high CXCR4 expression, LN metastases and poorly differentiated tumour are independent negative prognosis factors. In a combining analysis, patients with CXCR4 low /CXCR7 low tumour had a significantly shorter DFS and OS than patients with a CXCR7 high /CXCR4 high tumour. CXCR4 in resected PA may represent a valuable prognostic factor as well as an attractive target for therapeutic purpose.

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U-BIOPRED cohort n=91 epithelial brushings or biopsies IL-17 High Clinical phenotype Nasal polyps Smoking Antibiotic use Epithelial Gene Expression Profile Clinical phenotype FeNO Exacerbations Gene expression shared with psoriasis IDO1 IL1B DEFB4B S100A8, S100A9 PI3 CXCL3, CXCL8 CXCL10, CCL20 Gene signature SERPINB2 POSTN CLCA1 IL-13 High T cell infiltration Neutrophilia Eosinophilia IL-17-high asthma with features of a psoriasis immunophenotype From a the Respiratory,

The matrix metalloproteinases gelatinase A (MMP-2) and gelatinase B (MMP-9) are implicated in the physiological and pathological breakdown of several extracellular matrix proteins. In the present study, we show that long-chain fatty acids (e.g. oleic acid, elaidic acid, and cis-and trans-parinaric acids) inhibit gelatinase A as well as gelatinase B with K i values in the micromolar range but had only weak inhibitory effect on collagenase-1 (MMP-1), as assessed using synthetic or natural substrates. The inhibition of gelatinases depended on fatty acid chain length (with C18 > C16, C14, and C10), and the presence of unsaturations increased their inhibitory capacity on both types of gelatinase. Ex vivo experiments on human skin tissue sections have shown that micromolar concentrations of a long-chain unsaturated fatty acid (elaidic acid) protect collagen and elastin fibers against degradation by gelatinases A and B, respectively. In order to understand why gelatinases are more susceptible than collagenase-1 to inhibition by longchain fatty acids, the possible role of the fibronectin-like domain (a domain unique to gelatinases) in binding inhibitory fatty acids was investigated. Affinity and kinetic studies with a recombinant fibronectin-like domain of gelatinase A and with a recombinant mutant of gelatinase A from which this domain had been deleted pointed to an interaction of long-chain fatty acids with the fibronectin-like domain of the protease. Surface plasmon resonance studies on the interaction of longchain fatty acids with the three individual type II modules of the fibronectin-like domain of gelatinase A revealed that the first type II module is primarily responsible for binding these compounds. Matrix metalloproteinases (MMPs)1 compose a family of at least 23 related zinc-dependent endopeptidases (1) that are collectively able to degrade extracellular matrix proteins such as collagens, laminins, fibronectin, elastin, and proteoglycans. They are consequently implicated in physiological remodeling of connective tissue occurring in embryonic development and repair (2-4). Most of them are secreted as inactive proenzymes and are then extra-or pericellularly activated by other MMPs or serine proteinases (5). Their catalytic activities are strictly controlled by endogenous specific inhibitors designated as tissue inhibitors of metalloproteinases (TIMPs) (6) and also ␣ 2 -macroglobulin (7). The balance between activated MMPs and TIMPs determines the overall MMP proteolytic activity and consequently the extent of extracellular matrix degradation. Local disruption of the MMP-TIMP balance can lead to pathological degradative processes including rheumatoid arthritis, atherosclerosis, tumor growth, and metastasis (8 -10). MMPs are multidomain enzymes containing propeptide, catalytic and, except matrilysin (MMP-7), MMP-23, and endometase/matrilysin-2 (MMP-26), hemopexin-like domains. Gelatinase A (MMP-2) and gelatinase B (MMP-9) contain in addition three tandem copies of a 58-amino acid fibronectin type II (FN-II) modul...