Tumour cell thrombospondin-1 regulates tumour cell adhesion and invasion through the urokinase plasminogen activator receptor

We have previously shown that platelet-produced thrombospondin-1 up-regulates the urokinase plasminogen activator and its receptor and promotes tumour cell invasion. Although tumour cells produce thrombospondin-1 in vivo, they produce only minimal amounts of thrombospondin-1 in vitro. To determine the effect of tumour cell-produced thrombospondin-1 in the regulation of the plasminogen/plasmin system and tumour cell invasion, we studied THBS-1 -transfected MDA-MB-435 breast cancer cells that overexpress thrombospondin-1. The role of urokinase plasminogen receptor in thrombospondin-1-mediated adhesion and invasion was studied by antisense inhibition, enzymatic cleavage and antibody neutralization. Tumour cell adhesion to collagen and laminin was evaluated. Tumour cell invasion was studied in a modified Boyden chamber collagen invasion assay. Tumour cell thrombospondin-1 induced a 2–7 fold increase in urokinase plasminogen activator receptor and cell-associated urokinase plasminogen activator expression and a 50–65% increase in cell-associated urokinase plasminogen activator and plasmin activities. Furthermore, tumour cell thrombospondin-1 promoted tumour cell invasion and decreased tumour cell adhesion through up-regulation of urokinase plasminogen activator receptor-controlled urokinase plasminogen activator and plasmin activities. We conclude that tumour cell-produced thrombospondin-1 may play a critical role in the regulation of tumour cell adhesion and tumour cell invasion. © 2000 Cancer Research Campaig

Modeling transcription factor binding events to DNA using a random walker/jumper representation on a 1D/2D lattice with different affinity sites

Surviving in a diverse environment requires corresponding organism responses. At the cellular level, such adjustment relies on the transcription factors (TFs) which must rapidly find their target sequences amidst a vast amount of non-relevant sequences on DNA molecules. Whether these transcription factors locate their target sites through a 1D or 3D pathway is still a matter of speculation. It has been suggested that the optimum search time is when the protein equally shares its search time between 1D and 3D diffusions. In this paper, we study the above problem using a Monte Carlo simulation by considering a very simple physical model. A 1D strip, representing a DNA, with a number of low affinity sites, corresponding to non-target sites, and high affinity sites, corresponding to target sites, is considered and later extended to a 2D strip. We study the 1D and 3D exploration pathways, and combinations of the two modes by considering three different types of molecules: a walker that randomly walks along the strip with no dissociation; a jumper that represents dissociation and then re-association of a TF with the strip at later time at a distant site; and a hopper that is similar to the jumper but it dissociates and then re-associates at a faster rate than the jumper. We analyze the final probability distribution of molecules for each case and find that TFs can locate their targets fast enough even if they spend 15% of their search time diffusing freely in the solution. This indeed agrees with recent experimental results obtained by Elf et al. 2007 and is in contrast with theoretical expectation.Comment: 24 pages, 9 figure

Leukemia Inhibitory Factor Augments Neurotrophin Expression and Corticospinal Axon Growth after Adult CNS Injury

The cytokine leukemia inhibitory factor (LIF) modulates glial and neuronal function in development and after peripheral nerve injury, but little is known regarding its role in the injured adult CNS. To further understand the biological role of LIF and its potential mechanisms of action after CNS injury, effects of cellularly delivered LIF on axonal growth, glial activation, and expression of trophic factors were examined after adult mammalian spinal cord injury. Fibroblasts genetically modified to produce high amounts of LIF were grafted to the injured spinal cords of adult Fischer 344 rats. Two weeks after injury, animals with LIF-secreting cells showed a specific and significant increase in corticospinal axon growth compared with control animals. Furthermore, expression of neurotrophin-3, but not nerve growth factor, brain-derived neurotrophic factor, glia cell line-derived neurotrophic factor, or ciliary neurotrophic factor, was increased at the lesion site in LIF-grafted but not in control subjects. No differences in astroglial and microglial/macrophage activation were observed. Thus, LIF can directly or indirectly modulate molecular and cellular responses of the adult CNS to injury. These findings also demonstrate that neurotrophic molecules can augment expression of other trophic factors in vivo after traumatic injury in the adult CNS

A q-deformed Aufbau Prinzip

A building principle working for both atoms and monoatomic ions is proposed in this Letter. This principle relies on the q-deformed chain SO(4) > G where G = SO(3)_q

Enhancing the activity of platinum-based drugs by improved inhibitors of ERCC1–XPF-mediated DNA repair

Purpose: The ERCC1–XPF 5′–3′ DNA endonuclease complex is involved in the nucleotide excision repair pathway and in the DNA inter-strand crosslink repair pathway, two key mechanisms modulating the activity of chemotherapeutic alkylating agents in cancer cells. Inhibitors of the interaction between ERCC1 and XPF can be used to sensitize cancer cells to such drugs. Methods: We tested recently synthesized new generation inhibitors of this interaction and evaluated their capacity to sensitize cancer cells to the genotoxic activity of agents in synergy studies, as well as their capacity to inhibit the protein–protein interaction in cancer cells using proximity ligation assay. Results: Compound B9 showed the best activity being synergistic with cisplatin and mitomycin C in both colon and lung cancer cells. Also, B9 abolished the interaction between ERCC1 and XPF in cancer cells as shown by proximity ligation assay. Results of different compounds correlated with values from our previously obtained in silico predictions. Conclusion: Our results confirm the feasibility of the approach of targeting the protein–protein interaction between ERCC1 and XPF to sensitize cancer cells to alkylating agents, thanks to the improved binding affinity of the newly synthesized compounds

Generalized thermodynamics of q-deformed bosons and fermions

We study the thermostatistics of q-deformed bosons and fermions obeying the symmetric algebra and show that it can be built on the formalism of q-calculus. The entire structure of thermodynamics is preserved if ordinary derivatives are replaced by an appropriate Jackson derivative. In this framework, we derive the most important thermodynamic functions describing the q-boson and q-fermion ideal gases in the thermodynamic limit. We also investigate the semi-classical limit and the low temperature regime and demonstrate that the nature of the q-deformation gives rise to pure quantum statistical effects stronger than undeformed boson and fermion particles.Comment: 8 pages, Physical Review E in pres

Endothelial apoptotic activity of angiocidin is dependent on its polyubiquitin binding activity

We recently cloned the full-length cDNA of a tumour-associated protein. The recombinant protein expressed in bacteria and referred to as angiocidin has potent antitumour activity in vivo and in vitro. Angiocidin inhibits tumour growth and angiogenesis by inducing apoptosis in endothelial cells. Based on the sequence similarity of angiocidin to S5a, one of the major polyubiquitin recognition proteins in eukaryotic cells, we postulated that the antiendothelial activity of angiocidin could be due in part to its polyubiquitin binding activity. In support of this hypothesis, we show that angiocidin binds polyubiquitin in vivo with high affinity and colocalises with ubiquitinated proteins on the surface of endothelial cells. Binding is blocked with an antiubiquitin antibody. Angiocidin treatment of endothelial cells transfected with a proteasome fluorescent reporter protein showed a dose-dependent inhibition of proteasome activity and accumulation of polyubiquitinated proteins. Full-length angiocidin bound polyubiquitin while three angiocidin recombinant proteins whose putative polyubiquitin binding sites were mutated either failed to bind polyubiquitin or had significantly diminished binding activity. The in vitro apoptotic activity of these mutants correlated with their polyubiquitin binding activity. These data strongly argue that the apoptotic activity of angiocidin is dependent on its polyubiquitin binding activity

Experimental Treatments for Spinal Cord Injury: What you Should Know

Experiencing a spinal cord injury (SCI) is extremely distressing, both physically and psychologically, and throws people into a complex, unfamiliar world of medical procedures, terminology, and decision making. You may have already had surgery to stabilize the spinal column and reduce the possibility of further damage. You are understandably distressed about the functions you may have lost below the level of spinal injury. You wish to recover any lost abilities as soon as possible. You, your family, or friends may have searched the Internet for treatments and cures

Electronic energy migration in Microtubules

The repeating arrangement of tubulin dimers confers great mechanical strength to microtubules, which are used as scaffolds for intracellular macromolecular transport in cells and exploited in biohybrid devices. The crystalline order in a microtubule, with lattice constants short enough to allow energy transfer between amino acid chromophores, is similar to synthetic structures designed for light harvesting. After photoexcitation, can these amino acid chromophores transfer excitation energy along the microtubule like a natural or artificial light-harvesting system? Here, we use tryptophan autofluorescence lifetimes to probe energy hopping between aromatic residues in tubulin and microtubules. By studying how the quencher concentration alters tryptophan autofluorescence lifetimes, we demonstrate that electronic energy can diffuse over 6.6 nm in microtubules. We discover that while diffusion lengths are influenced by tubulin polymerization state (free tubulin versus tubulin in the microtubule lattice), they are not significantly altered by the average number of protofilaments (13 versus 14). We also demonstrate that the presence of the anesthetics etomidate and isoflurane reduce exciton diffusion. Energy transport as explained by conventional Förster theory (accommodating for interactions between tryptophan and tyrosine residues) does not sufficiently explain our observations. Our studies indicate that microtubules are, unexpectedly, effective light harvesters

Charge-density-wave instability in the Holstein model with quartic anharmonic phonons

The molecular-crystal model, that describes a one-dimensional electron gas interacting with quartic anharmonic lattice vibrations, offers great potentials in the mapping of a relatively wide range of low-dimensional fermion systems coupled to optical phonons onto quantum liquids with retarded interactions. Following a non-perturbative approach involving non-Gaussian partial functional integrations of lattice degrees of freedom, the exact expression of the phonon-mediated two-electron action for this model is derived. With the help of Hubbard-Stratonovich transformation the charge-density-wave instability is examined in the sequel, with particular emphasis on the effect of the quartic anharmonic phonons on the charge-density-wave transition temperature.Comment: 12 pages, 3 figure