The contractile properties of vaginal myofibroblasts: Is the myofibroblasts contraction force test a valuable indication of future prolapse development?

Using a specific myofibroblast contraction test, we try to predict future utero-vaginal prolapse development in young primiparae women. We compare myofibroblast cultures of the vaginal wall in primiparae women (group 1), young multiparae women (group 2) and older multiparae women (group 3) who were operated on for severe utero-vaginal prolapse. A myofibroblast-mediated collagen gel contraction assay determined a contraction factor that was compared in the three groups of women. The myofibroblasts contraction factor after 24 and 48 hours was significantly higher in group 1 women (2.4 ± 0.6/4.4 ± 1.9) compared to group 2 (1.6 ± 0.3/ 1.8 ± 0.1) andgroup 3 (1.6 ± 0.3/1.8 ± 0.3), but showed no differences in group 1 women without (2.1 ± 0.5/3.5 ± 1.9) and with (2.7 ± 0.6/5.1 ± 1.7) cystocoele. Vaginal myofibroblasts of young women show better contraction forces than young women with severe utero-vaginal prolapse. The latter have a myofibroblast contraction factor similar to those of older post-menopausal women operated for the same conditio

Experience with the Multi-Year Implementation of an Industrial Control System

In 1990, CERN passed a multi-year purchasing and installation contract for the LEP 200 Cryogenics control system with ABB, one of the world's leading suppliers of integrated Distributed Control Systems (DCS). A financial framework provided over a period of eight years the required supplies. These were called up with so called "Release Orders", taking into account the latest technical developments. The issues and experiences with such a new approach and the resulting control system are described

Cryogenic Facilities at 1.9 K for the Reception of the Superconducting Wires and Cables of the LHC Dipoles Magnets

CERN's LHC project has moved to an implementation phase. The fabrication of 1600 high-field superconducting magnets operating at 1.9 K will require about 6400 km of Nb-Ti cables. A cryogenic test facility has therefore been set up in order, on the one hand, to verify the quality of individual wires and, on the other hand, to control the critical current of the assembled cables. The facility is composed of a helium liquefier, a transfer line, a dewar and pumps. The paper describes the fully automatic operation of this installation and the different test cycles applied to these wires and cables

Fibroblast activation protein-α in fibrogenic disorders and cancer: more than a prolyl-specific peptidase?

Fibroblast activation protein-α (FAP-α) belongs to the family of prolyl-specific serine proteases. FAP-α displays both exopeptidase and endopeptidase/gelatinase/collagenase activities. FAP-α protein and/or activity have been associated with fibrosis, inflammation and cancer, but the protein is undetectable in most normal tissues. FAP-α is selectively expressed at sites of tissue remodeling and repair and enhances tumor progression, suggesting that this protease may be a therapeutic target to treat human disorders associated with fibrotic dysregulation. Areas covered: In this review, we summarize the mechanisms driving tissue fibrosis and describe some of the enzymes involved in fibrosis, concentrating on FAP-α. We describe its enzymatic properties, discuss the tools developed to control its activity and the problem of selectivity toward the other proteases of the family and outline its potential biological substrates. We also consider non-enzymatic functions of this protein and suggest that repression of FAP-α expression may represent therapeutic options. Expert opinion: Questions remain regarding the biological functions of FAP-α, either dependent or independent of its enzyme activity. However, as progress is underway to develop FAP-α-specific inhibitors and therapeutic antibodies, its role in diseases associated with fibrosis is starting to emerge, ultimately leading to novel therapeutic options for inflammatory and oncologic diseases

P719 Determinants of tobacco consumption in the Swiss IBD cohort

Background: Tobacco consumption is an important environmental factor in inflammatory bowel diseases (IBD). Our aim was to identified characteristics associated with smoking in Crohn's disease (CD) and Ulcerative colitis (UC). Methods: Adult UC and CD patients included in the Swiss IBD cohort study (SIBDCS) from Nov. 2006 to Nov. 2015 were asked about their smoking status. Patients were separated in two groups (active smokers vs. non-smokers). A logistic regression analysis was performed with smoking as main outcome

Endothelin-Receptor Antagonists beyond Pulmonary Arterial Hypertension: Cancer and Fibrosis.

The endothelin axis and in particular the two endothelin receptors, ETA and ETB, are targets for therapeutic intervention in human diseases. Endothelin-receptor antagonists are in clinical use to treat pulmonary arterial hypertension and have been under clinical investigation for the treatment of several other diseases, such as systemic hypertension, cancer, vasospasm, and fibrogenic diseases. In this Perspective, we review the molecules that have been evaluated in human clinical trials for the treatment of pulmonary arterial hypertension, as well as other cardiovascular diseases, cancer, and fibrosis. We will also discuss the therapeutic consequences of receptor selectivity with regard to ETA-selective, ETB-selective, or dual ETA/ETB antagonists. We will also consider which chemical characteristics are relevant to clinical use and the properties of molecules necessary for efficacy in treating diseases against which known molecules displayed suboptimal efficacy

Functionalized pyrrolidines as alpha-mannosidase inhibitors and growth inhibitors of human glioblastoma and melanoma cells

New substituted pyrrolidine-3,4-diol derivatives were prepared from D-(-)- and L-(+)-phenyl glycinol. The influence of the configuration and the substitution of the lateral side chain of these derivatives on the inhibition of 25 commercial glycosidases were determined. (2R,3R,4S)-2-({[(1R)-2-Hydroxy-1-phenylethyl]amino}methyl)pyrrolidine-3,4-diol ((+)-7a) was a potent and selective inhibitor of jack bean alpha-mannosidase (Ki = 135 nM). However, when evaluated on human tumor cells, 7a, and the reference compound swainsonine, did not efficiently inhibit the growth of glioblastoma cells. Further derivatization of the hydroxyl group with lipophilic groups to increase bioavailability improved their growth inhibitory properties for human glioblastoma and melanoma cells. In particular the 4-bromobenzoyl derivative 26 demonstrated high efficacy for human tumor cells whereas primary human fibroblasts were less sensitive to 26. Therefore functionalized pyrrolidines have the potential to inhibit the growth of tumor cells and display selectivity for tumor cells compared to normal cells

Renin and angiotensinogen expression and functions in growth and apoptosis of human glioblastoma

The expression and function in growth and apoptosis of the renin-angiotensin system (RAS) was evaluated in human glioblastoma. Renin and angiotensinogen (AGT) mRNAs and proteins were found by in situ hybridisation and immunohistochemistry in glioblastoma cells. Angiotensinogen was present in glioblastoma cystic fluids. Thus, human glioblastoma cells produce renin and AGT and secrete AGT. Human glioblastoma and glioblastoma cells expressed renin, AGT, renin receptor, AT(2) and/or AT(1) mRNAs and proteins determined by RT-PCR and/or Western blotting, respectively. The function of the RAS in glioblastoma was studied using human glioblastoma cells in culture. Angiotensinogen, des(Ang I)AGT, tetradecapaptide renin substrate (AGT1-14), Ang I, Ang II or Ang III, added to glioblastoma cells in culture, did not modulate their proliferation, survival or death. Angiotensin-converting enzyme inhibitors did not diminish glioblastoma cell proliferation. However, the addition of selective synthetic renin inhibitors to glioblastoma cells decreased DNA synthesis and viable tumour cell number, and induced apoptosis. This effect was not counterbalanced by concomitant addition of Ang II. In conclusion, the complete RAS is expressed by human glioblastomas and glioblastoma cells in culture. Inhibition of renin in glioblastoma cells may be a potential approach to control glioblastoma cell proliferation and survival, and glioblastoma progression in combination therapy