FGF-1 and FGF-2 modulate the E-cadherin/catenin system in pancreatic adenocarcinoma cell lines

Fibroblast growth factors (FGFs) and fibroblast growth factor receptors (FGFRs) have been increasingly recognized to play an important role in the pathobiology of pancreatic malignancy. We have investigated the effects of FGF-1 and FGF-2 on the behaviour and adhesion properties of human pancreatic adenocarcinoma cell lines (BxPc3, T3M4 and HPAF) that were previously characterised for the expression of FGFRs. Here we show that exposure to FGF-1 and FGF-2 leads to significant and dose-dependent increase in E-cadherin-dependent cell-cell adhesion, tubular differentiation, and a reduced capacity to invade collagen gels. FGF stimulation produces phosphorylation of E-cadherin and β-catenin on tyrosine residues, as well as increased E-cadherin localisation to the cytoplasmic membrane and association with FGFR1 demonstrable by coimmunoprecipitation. These results demonstrate that FGF-1 and FGF-2 may be involved in the regulation of cell adhesion, differentiation and invasion of pancreatic cancer. © Cancer Research Campaign http://www.bjcancer.co

Optimisation of conditions for detection of activated oncogenes by transfection of NIH 3T3 cells.

Optimisation of conditions for detection of activated oncogenes by transfection of NIH 3T3 cells

Design Considerations for a Dedicated Gravity Recovery Satellite Mission Consisting of Two Pairs of Satellites

Future satellite missions dedicated to measuring time-variable gravity will need to address the concern of temporal aliasing errors; i.e., errors due to high-frequency mass variations. These errors have been shown to be a limiting error source for future missions with improved sensors. One method of reducing them is to fly multiple satellite pairs, thus increasing the sampling frequency of the mission. While one could imagine a system architecture consisting of dozens of satellite pairs, this paper explores the more economically feasible option of optimizing the orbits of two pairs of satellites. While the search space for this problem is infinite by nature, steps have been made to reduce it via proper assumptions regarding some parameters and a large number of numerical simulations exploring appropriate ranges for other parameters. A search space originally consisting of 15 variables is reduced to two variables with the utmost impact on mission performance: the repeat period of both pairs of satellites (shown to be near-optimal when they are equal to each other), as well as the inclination of one of the satellite pairs (the other pair is assumed to be in a polar orbit). To arrive at this conclusion, we assume circular orbits, repeat groundtracks for both pairs of satellites, a 100-km inter-satellite separation distance, and a minimum allowable operational satellite altitude of 290 km based on a projected 10-year mission lifetime. Given the scientific objectives of determining time-variable hydrology, ice mass variations, and ocean bottom pressure signals with higher spatial resolution, we find that an optimal architecture consists of a polar pair of satellites coupled with a pair inclined at 72deg, both in 13-day repeating orbits. This architecture provides a 67% reduction in error over one pair of satellites, in addition to reducing the longitudinal striping to such a level that minimal post-processing is required, permitting a substantial increase in the spatial resolution of the gravity field products. It should be emphasized that given different sets of scientific objectives for the mission, or a different minimum allowable satellite altitude, different architectures might be selected

Expression of collagenase (MMP2), stromelysin (MMP3) and tissue inhibitor of the metalloproteinases (TIMP1) in pancreatic and ampullary disease.

It is now recognised that epithelial-stromal interactions are important in a wide range of disease processes including neoplasia and inflammation. Metalloproteinases are central to matrix degradation and remodelling, which are key events in tumour invasion and metastasis and may also be involved in tissue changes occurring in chronic inflammation. Immunohistochemistry was performed on sections from 50 patients with pancreatic cancer (n = 27), ampullary cancer (n = 12), low bile duct cancer (n = 3), neuroendocrine tumours (n = 3) and chronic pancreatitis (n = 5), using antibodies raised against collagenase (MMP2), stromelysin (MMP3) and tissue inhibitor of metalloproteinase (TIMP1) and developed using the avidin-biotin complex method. Abundance of MMP2, MMP3 and TIMP1 was greater in pancreatic and ampullary cancer than any other pathology and immunoreactivity in the malignant epithelial cells in pancreatic and ampullary cancer was greater than in the stromal tissues (in pancreatic cancer: MMP2 100% vs 37%, MMP3 93% vs 15%, TIMP1 93% vs 4%, P < 0.0001). There were strong correlations between the immunoreactivity of the two antibodies for MMP2 (P < 0.0001), between MMP2 and TIMP1 (P < 0.0001) and between MMP3 and TIMP1 (P < 0.0001). The immunoreactivity for TIMP1 in pancreatic and ampullary cancers with lymph node metastases was significantly less compared with those cases without lymph node metastases (P < 0.02) and there was an association between increased immunoreactivity for MMP2 and the degree of tumour differentiation (P < 0.01). The results implicate MMP2, MMP3 and TIMP1 in the invasive phenotype of pancreatic and ampullary cancer

Structure and expression of nuclear oncogenes in multi-stage thyroid tumorigenesis.

We have investigated the possibility that structural alterations of the 'nuclear' oncogene family (c-myc, N-myc, L-myc, fos, myb and p53) leading to aberrant expression might, as in several other tumour types, play a role in the multi-stage development of tumorigenesis in the human thyroid follicular cell. Direct analysis of expression by slot and Northern blot RNA hybridisation showed that normal thyroid expresses surprisingly high levels of fos, and to a lesser extent c-myc, c-myc expression was markedly increased in all tumours, both benign and malignant, but no increase was seen in any other nuclear oncogene. fos expression was reduced specifically in one type of malignant tumour-follicular carcinoma-in inverse correlation with differentiation. Southern blot analysis showed no evidence of rearrangement or amplification of c-myc, or of any other 'nuclear' oncogene in any thyroid tumour. We conclude that there is no evidence that a primary abnormality of these genes plays a role in thyroid follicular cell tumorigenesis and suggest that the observed changes in expression can be adequately explained as secondary consequences of the tumour phenotype

Sensitization of tumour cells to lysis by virus-specific CTL using antibody-targeted MHC class I/peptide complexes

A number of cell surface molecules with specificity to tumour cells have been identified and monoclonal antibodies (mAb) to some of these antigens have been used for targeting tumour cells in vivo. We have sought to link the powerful effector mechanisms of cytotoxic T-cells with the specificity of mAb, by targeting recombinant HLA class I molecules to tumour cells using an antibody delivery system. Soluble recombinant MHC class I/peptide complexes including HLA-A2.1 refolded around an immunodominant peptide from the HIV gag protein (HLA-A2/gag) were synthesized, and the stability of these complexes at 37°C was confirmed by enzyme-linked immunosorbent assay using a conformation-specific antibody. MHC class I-negative lymphoma cells (Daudi) were labelled with a biotinylated mAb specific for a cell surface protein (anti-CD20) then linked to soluble biotinylated HLA-A2/gag complexes using an avidin bridge. Flow cytometry revealed strong labelling of lymphoma cells with HLA-A2/gag complexes (80-fold increase in mean channel fluorescence). CTL specific for HLA-A2/gag efficiently lysed complex-targeted cells, while control CTL (specific for an HLA-A2.1-restricted epitope of melan-A) did not. Similarly, SK-mel-29 melanoma cells were also efficiently lysed by HLA-A2/gag-specific CTL when HLA-A2/gag complexes were linked to their surface via the HMW-MAA specific anti-melanoma antibody 225.28s. With further consideration to the in vivo stability of the MHC class I/peptide complexes, this system could prove a new strategy for the immunological therapy of cancer. © 2000 Cancer Research Campaig

Duality in String Cosmology

Scale factor duality, a truncated form of time dependent T-duality, is a symmetry of string effective action in cosmological backgrounds interchanging small and large scale factors. The symmetry suggests a cosmological scenario ("pre-big-bang") in which two duality related branches, an inflationary branch and a decelerated branch are smoothly joined into one non-singular cosmology. The use of scale factor duality in the analysis of the higher derivative corrections to the effective action, and consequences for the nature of exit transition, between the inflationary and decelerated branches, are outlined. A new duality symmetry is obeyed by the lowest order equations for inhomogeneity perturbations which always exist on top of the homogeneous and isotropic background. In some cases it corresponds to a time dependent version of S-duality, interchanging weak and strong coupling and electric and magnetic degrees of freedom, and in most cases it corresponds to a time dependent mixture of both S-, and T-duality. The energy spectra obtained by using the new symmetry reproduce known results of produced particle spectra, and can provide a useful lower bound on particle production when our knowledge of the detailed dynamical history of the background is approximate or incomplete.Comment: 6 pages, no figures, latex2e using ltwol2e.sty. Based on talks at the 44'th annual meeting of the Israel Physical Society, Apr 8, 1998, Rehovot, Israel, and ICHEP98, 23-29 July, Vancouver, BC, Canada, and second conf. on Quantum Aspects of Gauge Theories, Supersymmetry and Unification, Sept 21-26, 1998, Corfu, Greece. To be published in the proceeding

Spectral up- and downshifting of Akhmediev breathers under wind forcing

We experimentally and numerically investigate the effect of wind forcing on the spectral dynamics of Akhmediev breathers, a wave-type known to model the modulation instability. We develop the wind model to the same order in steepness as the higher order modifcation of the nonlinear Schroedinger equation, also referred to as the Dysthe equation. This results in an asymmetric wind term in the higher order, in addition to the leading order wind forcing term. The derived model is in good agreement with laboratory experiments within the range of the facility's length. We show that the leading order forcing term amplifies all frequencies equally and therefore induces only a broadening of the spectrum while the asymmetric higher order term in the model enhances higher frequencies more than lower ones. Thus, the latter term induces a permanent upshift of the spectral mean. On the other hand, in contrast to the direct effect of wind forcing, wind can indirectly lead to frequency downshifts, due to dissipative effects such as wave breaking, or through amplification of the intrinsic spectral asymmetry of the Dysthe equation. Furthermore, the definitions of the up- and downshift in terms of peak- and mean frequencies, that are critical to relate our work to previous results, are highlighted and discussed.Comment: 30 pages, 11 figure