b-tagging in DELPHI at LEP

Abstract: The standard method used for tagging b-hadrons in the DELPHI experiment at the CERN LEP Collider is discussed in detail. The main ingredient of b-tagging is the impact parameters of tracks, which relies mostly on the vertex detector. Additional information, such as the mass of particles associated to a secondary vertex, significantly improves the selection efficiency and the background suppression. The paper describes various discriminating variables used for the tagging and the procedure of their combination. In addition, applications of b-tagging to some physics analyses, which depend crucially on the performance and reliability of b-tagging, are described briefly

Prompt K_short production in pp collisions at sqrt(s)=0.9 TeV

The production of K_short mesons in pp collisions at a centre-of-mass energy of 0.9 TeV is studied with the LHCb detector at the Large Hadron Collider. The luminosity of the analysed sample is determined using a novel technique, involving measurements of the beam currents, sizes and positions, and is found to be 6.8 +/- 1.0 microbarn^-1. The differential prompt K_short production cross-section is measured as a function of the K_short transverse momentum and rapidity in the region 0 < pT < 1.6 GeV/c and 2.5 < y < 4.0. The data are found to be in reasonable agreement with previous measurements and generator expectations.Comment: 6+18 pages, 6 figures, updated author lis

Sodium Pancratistatin 3,4-O-Cyclic Phosphate, a water soluble synthetic derivative of Pancratistatin, is highly effective in a human colon tumour model

Sodium pancratistatin 3,4- O-cyclic phosphate ( 2) is a novel water-soluble synthetic derivative of pancratistatin ( 1), a natural alkaloid constituent of Amaryllidaceae plants, that exhibits good cytostatic and antineoplastic activity but is highly insoluble. Unlike most other natural alkaloids it does not act by binding to tubulin, and its mechanism of action has yet to be fully elucidated. Here the efficacy of 2 in a human colon adenocarcinoma model, DLD-1, and some understanding of its mode of action are investigated. Agreeing with previous studies, low cytotoxicity in vitro was seen for 2 with IC 50's of 253 and 19.7 microM for 1 and 96 h exposures, respectively. However in vivo the compound caused statistically significant tumor growth delays ( p < 0.01) at its maximum tolerated dose, and significant vascular shutdown and tumor necrosis were observed. Like 1, the compound appeared to have an unconventional mechanism of action with no effect on microtubule structure, yet causing a G 2/M block, while it was seen to disrupt mitochondrial function. The mechanism of action of 1 and 2 appears to be similar. Thus compound 2, being considerably more soluble than 1, has good potential as an anticancer agent, and further investigation is warranted

Expression of matrix metalloproteinase-10 in human bladder transitional cell carcinoma

OBJECTIVES: To analyze matrix metalloproteinase-10 (MMP-10) expression in transitional cell carcinoma (TCC) of the bladder, evaluate the correlations between MMP-10 protein expression and clinicopathologic parameters, and address the viability of MMP-10 as a therapeutic target for TCC. MMP-mediated degradation of the extracellular matrix is an important factor in the pathogenesis of tumorigenesis and metastasis. METHODS: Using immunohistochemistry, the expression of MMP-10 was assessed using both tissue microarrays and whole sections of archival tissue specimens representative of all grades and stages of human bladder TCC (n = 60). MMP-10 expression was also assessed in histologically normal human bladder tissue (n = 10). The immunostaining results for MMP-10 expression were examined for correlations with tumor grade and stage. RESULTS: Unlike most MMPs, MMP-10 was localized primarily in the tumor mass as opposed to the tumor stroma and was detectable in all grades and stages of TCC. Significantly greater levels of MMP-10 protein were observed in superficial (pTa, pT1; n = 38) tumors than in normal bladder tissue (P = 0.01). In contrast to the proposed role of MMPs in tumor invasion, no significant difference was observed between muscle-invasive tumors (pT2 or worse; n = 22) and histologically normal bladder tissue (P = 0.50). MMP-10 expression showed no significant correlation with tumor grade. CONCLUSIONS: The data from our study showed that, unlike most MMPs, MMP-10 was not associated with tumor aggression or invasion. Our results suggest that MMP-10 protein levels are significantly greater in the earlier stages of TCC development

Development of a novel tumor-targeted vascular disrupting agent activated by Membrane-Type Matrix Metalloproteinases

Vascular disrupting agents (VDA) offer a strategy to starve solid tumors of nutrients and oxygen concomitant with tumor shrinkage. Several VDAs have progressed into early clinical trials, but their therapeutic value seems to be compromised by systemic toxicity. In this report, we describe the design and characterization of a novel VDA, ICT2588, that is nontoxic until activated specifically in the tumor by membrane-type 1 matrix metalloproteinase (MT1-MMP). HT1080 cancer cells expressing MT1-MMP were selectively chemosensitive to ICT2588, whereas MCF7 cells that did not express MT1-MMP were nonresponsive. Preferential hydrolysis of ICT2588 to its active metabolite (ICT2552) was observed in tumor homogenates of HT1080 relative to MCF7 homogenates, mouse plasma, and liver homogenate. ICT2588 activation was inhibited by the MMP inhibitor ilomastat. In HT1080 tumor-bearing mice, ICT2588 administration resulted in the formation of the active metabolite, diminution of tumor vasculature, and hemorrhagic necrosis of the tumor. The antitumor activity of ICT2588 was superior to its active metabolite, exhibiting reduced toxicity, improved therapeutic index, enhanced pharmacodynamic effect, and greater efficacy. Coadministration of ICT2588 with doxorubicin resulted in a significant antitumor response (22.6 d growth delay), which was superior to the administration of ICT2588 or doxorubicin as a single agent, including complete tumor regressions. Our findings support the clinical development of ICT2588, which achieves selective VDA targeting based on MT-MMP activation in the tumor microenvironment

MMP-10 is overexpressed, proteolytically active and a potential target for therapeutic intervention in human lung carcinomas

Matrix metalloproteinase (MMP)-mediated degradation of the extracellular matrix is a major factor for tumor development and expansion. This study analysed MMP-10 protein expression and activity in human lung tumors of various grade, stage, and type to address the relationship between MMP-10 and tumor characteristics and to evaluate MMP-10 as a therapeutic target in non small cell lung carcinoma (NSCLC). Unlike the majority of MMPs, MMP-10 was located in the tumor mass as opposed to tumor stroma. MMP-10 protein was observed at low levels in normal human lung tissues and at significantly higher levels in all types of NSCLC. No correlation was observed between MMP-10 protein expression and tumor type, stage, or lymph node invasion. To discriminate between active and inactive forms of MMP-10 in samples of human NSCLC, we have developed an ex vivo fluorescent assay. Measurable MMP-10 activity was detected in 42 of 50 specimens of lung cancer and only 2 of 10 specimens of histologically normal lung tissue. No relationship was observed between MMP-10 activity levels and clinicopathologic characteristics. Our results suggest that MMP-10 is expressed and active at high levels in human NSCLC compared to normal lung tissues, and, as such, is a potential target for the development of novel therapeutics for lung cancer treatment