Interaction of tumor cells and immune system in the metastatic process

The metastatic process is rather complicated and relatively inefficient. Millions of tumor cells are constantly shedding from the primary tumor into the blood stream, but very few of them are able to form metastatic tumors in the different organs or tissues of the host. It is widely accepted that metastatic cells have to possess a complex array of various properties that allow them to complete the metastatic cascade. The realization of the metastatic potential largely depends on the ability of tumor cells to evade host defense mechanisms. The potential role of specific and nonspecific immune mechanisms in the control of metastatic spread and growth is the subject of the present review. A better understanding of the mechanisms of antimetastatic defense is of prime importance for development of efficient immunotherapeutic methods for the treatment and eradication of disseminated tumor metastases.     

Self-organization toward criticality in the Game of Life.

Life seems to be at the border between order and chaos. The Game of Life, which is a cellular automation to mimic life, also lies at the transition between ordered and chaotic structures. Kauffman recently that the organizations at the edge of chaos may be the characteristic target of selection for systems able to coordinate complex tasks and adapt. In this paper, we present the idea of perpetual disequilibration proposed by Gunji and others as a general principle governing self-organization of complex systems towards the critical state lying at the border of order and chaos. The rule for the Game of Life has the minimum degree of perpetual disequilibrium among 2(18) rules of the class to which it belongs.     

Interactions between species and environments from incomplete information

There are two contradictory aspects of the adaptive process in evolution. The first is that species must optimally increase their own fitness in a given environment. The second is that species must maintain their variation to be ready to respond to changing environments. In a strict sense, these two aspects might consider to be mutually exclusive. If species are optimally adapted, then the variation in the species that is suboptimal decreases and vice versa. To resolve this dilemma, species must find a balance between optimal adaptation and robust adaptation. Finding the balance between these processes requires both the local and global complete, static information. However, the balance between the processes must be dynamic. In this study, we propose a model that illustrates dynamic negotiation between the global and local information using lattice theory. The dynamic negotiation between these two levels results in an overestimate of fitness for each species. The overestimation of fitness in our model represents the multiplicity of fitness which is sometimes discussed as the exaptation. We show that species in our model demonstrate the power law of the lifespan distribution and 1/f fluctuation for the adaptive process. Our model allows for a balance between optimal adaptation and robust adaptation without any arbitrary parameters.     

Bmx Tyrosine Kinase Has a Redundant Function Downstream of Angiopoietin and Vascular Endothelial Growth Factor Receptors in Arterial Endothelium

The Bmx gene, a member of the Tec tyrosine kinase gene family, is known to be expressed in subsets of hematopoietic and endothelial cells. In this study, mice were generated in which the first coding exon of the Bmx gene was replaced with the lacZ reporter gene by a knock-in strategy. The homozygous mice lacking Bmx activity were fertile and had a normal life span without an obvious phenotype. Staining of their tissues using beta-galactosidase substrate to assess the sites of Bmx expression revealed strong signals in the endothelial cells of large arteries and in the endocardium starting between days 10.5 and 12.5 of embryogenesis and continuing in adult mice, while the venular endothelium showed a weak signal only in the superior and inferior venae cavae. Of the five known endothelial receptor tyrosine kinases tested, activated Tie-2 induced tyrosyl phosphorylation of the Bmx protein and both Tie-2 and vascular endothelial growth factor receptor 1 (VEGFR-1) stimulated Bmx tyrosine kinase activity. Thus, the Bmx tyrosine kinase has a redundant role in arterial endothelial signal transduction downstream of the Tie-2 and VEGFR-1 growth factor receptors.     

H-2 antigen expression and sensitivity of BL6 melanoma cells to natural killer cell cytotoxicity

The sensitivity of H-2b-high and H-2b-low variants of BL6 melanoma to the cytotoxic action of NK and lymphokine-activated killer cells was investigated. BL6 mouse melanoma cells lack detectable H-2Kb and had low levels of expression of H-2Db Ag. The BL6T2 variant cells, obtained after treatment of BL6 cells with mutagen N-methyl-N-nitro-N'-nitro-soguanidine, had relatively high levels of expression of class I H-2b Ag. Poly(I:C)-stimulated spleen cells of nude mice were highly cytotoxic for BL6T2, whereas H-2b-low BL6 cells were less sensitive to NK activity in an 18-h 51Cr-release assay. Similar results were obtained after 4-h incubation of radio-labeled tumor cells with IL-2-activated effector cells. In contrast, both lines were equally sensitive to lysis by purified granules derived from rat large granular lymphocytes (LGL) or by macrophages. By using various clones selected from BL6 or BL6T2 cells, it was found that BL6 or BL6T2 clones with low H-2b Ag expression were less sensitive to lysis by NK cells than H-2b-high clones. After IFN treatment of either BL6 or BL6T2, the target cells became more resistant to lysis by either NK cells or by purified LGL granules. IFN-treated BL6 cells had substantially increased expression of H-2b Ag and in this respect became similar to untreated BL6T2. However, IFN-treated BL6 cells were more resistant than BL6T2 cells to lysis by NK cells and LGL granules, suggesting that augmentation of H-2b Ag expression and NK resistance could be two independent IFN-induced effects. With a cold target inhibition assay, it was found that BL6T2 or its H-2 positive clones were highly competitive and inhibited the cytotoxic activity of NK and lymphokine-activated killer cells against radiolabeled YAC-1 and BL6T2, whereas BL6 cells or H-2-negative clones of BL6T2 and BL6 lines showed poor competitive ability. Thus, our data indicate that the NK resistance of H-2-low BL6 cells may be due to a paucity of NK recognizable determinants. N-Methyl-N-nitro-N'-nitroguanidine treatment of BL6 melanoma cells was associated with an increase in class I H-2b Ag expression and NK sensitivity, suggesting the involvement of class I MHC Ag in the sensitivity of tumor cells to NK cell-mediated cytotoxicity.     

Synthesis and structure-activity relationship of RXR antagonists based on the diazepinylbenzoic acid structure

Synthesis and structure-activity relationship of RXR antagonists employing a diazepinylbenzoic acid scaffold are described. Of those antagonists, sulfonamide derivatives (6v and 6w) reveal a high antagonistic activity and good pharmacokinetic properties.     

Novel scaffold for cathepsin K inhibitors

Pyrrolopyrimidine, a novel scaffold, allows to adjust interactions within the S3 subsite of cathepsin K. The core intermediate 10 facilitated the P3 optimization and identified highly potent and selective cathepsin K inhibitors 11-20.     

Synthesis and structure-activity relationship of novel RXR antagonists: orally active anti-diabetic and anti-obesity agents

A series of diazepinylbenzoic acid derivatives were synthesized and tested in the inhibition assay of the transactivation of RXR. Oral treatment of cyano derivatives (16f) was found to show anti-diabetic and anti-obesity effects in KK-A(y) mice.     

Emergence of morphological order in the network formation of Physarum polycephalum

Emergence in a system appears through the interaction of its components, giving rise to higher order or complexity in the system. We tested for the presence of emergent properties in a biological system using the simplest biological entity of a unicellular organism; the plasmodium of Physarum polycephalum, a giant unicellular amoeboid organism that forms a network-like tubular structure connecting its food sources. We let two plasmodium networks within a single cell interact with each other, and observed how the intracellular interaction affected the morphologenesis of the plasmodium networks. We found that the two networks developed homologous morphology. We further discuss the presence of autonomous and emergent properties in homologous network formation.