Solution structure of acidic fibroblast growth factor bound to 1,3, 6-naphthalenetrisulfonate: a minimal model for the anti-tumoral action of suramins and suradistas

Recent data show that anti-angiogenesis may provide a promising route to treat cancer. Fibroblast growth factors (FGFs) are powerful angiogenic polypeptides, whose mitogenic activity requires the presence of heparin-like compounds. It has been shown that angiogenesis promoted by FGFs on inhibition by monoclonal antibodies and antisense targeting can also inhibit tumour growth. Derivatives of suramin, a polysulfonated binaphthyl urea and binaphthylsulfonated derivatives of distamycin, suradistas, constitute an important group of potential anti-cancer agents. These compounds compete with heparin in forming tight complexes with FGFs. This inhibits the recognition of these growth factors by their tyrosine kinase membrane receptors thereby suppressing their angiogenic activity. Here we show that 1,3,6-naphthalenetrisulfonate, a common chemical function of the suramins and suradistas with the highest anti-angiogenic activity inhibits the mitogenic activity of acidic fibroblast growth factor, and that this inhibition is relieved by increasing concentrations of heparin in the assay. We have also solved the three-dimensional structure in solution of the protein complexed to this compound. The structural data provide clues that may help in understanding the inhibitory effect of suramins and suradistas, and could contribute to the development of new anti-tumoral drugs.     

Cell proliferation and cancer

The discovery that phosphorylation of selected proteins by cyclin-dependent kinases is the engine which makes the cycle run provides a new image of the control of proliferation and of its deregulation. The high conservation of this machinery in the different eukaryotic organisms emphasizes its early origin and its importance for life. It also makes the extrapolation of findings between different species feasible. The control of proliferation relies basically on accelerating and braking mechanisms which act on the engine driving the cycle. This review particularly stresses the importance of checkpoint or tumor suppressor pathways as transduction systems of negative signals which may induce a cycle braking operation. They prevent any important cycle transition, as the initiation of proliferation, that of replication, mitosis, etc., until the DNA and other cellular conditions make such a progression safe. These checkpoint pathways are able to recognize and transduce signals about the adequacy of initiating or continuing proliferation for a cell at a particular time, under a particular set of external and internal conditions. Crucial components of these pathways are proteins encoded by some of the checkpoint genes that evaluate the final balance of mitogenic and antimitogenic pathways reaching them and, if the balance is negative, they prevent temporarily cycle inititation or its progression by inhibiting the corresponding cyclin-dependent kinases. On the other hand, when the balance becomes positive, they allow the activation of the cyclin-dependent kinases. Uncontrolled cell proliferation associated with cancer always depends on the functional abrogation of at least one of the checkpoint pathways. The checkpoint or tumor suppressor protein p53 is one of the proteins in them, and mutations in the gene encoding it are present in more than half of all human tumours. The review touches new pharmacological strategies which have been opened by the discovery of portions of some of the signal transduction cascades involved in the transient brake of cell proliferation. Restoration of checkpoint pathways either prevents further proliferation of cells with damaged genome until repair is over or, alternatively, the dismantling of these checkpoints induce those cells to commit suicide (apoptosis). The fact that both restoration and dismantling of checkpoint pathways sensitive to DNA damage have not disturbing effects on any other proliferating cell with undamaged DNA makes these selective strategies promissing.     

The activation of fibroblast growth factors (FGFs) by glycosaminoglycans: influence of the sulfation pattern on the biological activity of FGF-1

Six synthetic heparin-like oligosaccharides have been used to investigate the effect of the oligosaccharide sulfation pattern on the stimulation of acidic fibroblast growth factor (FGF-1) induced mitogenesis signaling and the biological significance of FGF-1 trans dimerization in the FGF-1 activation process. It has been found that some molecules with a sulfation pattern that does not contain the internal trisaccharide motif, which has been proposed for high affinity for FGF-1, stimulate FGF-1 more efficiently than those with the structure of the regular region of heparin. In contrast to regular region oligosaccharides, in which the sulfate groups are distributed on both sides of their helical three-dimensional structures, the molecules containing this particular sulfation pattern display the sulfate groups only on one side of the helix. These results and the fact that these oligosaccharides do not promote FGF-1 dimerization according to sedimentation-equilibrium analysis, confirm the importance of negative-charge distribution in the activation process and strongly suggest that FGF dimerization is not a general and absolute requirement for biological activity.     

Low-density incomplete <Emphasis Type="Italic">LDL</Emphasis><Superscript><Emphasis Type="Italic">T</Emphasis></Superscript> factorizations

A particular class of incomplete factorizations is proposed as preconditioners for the linear system Ax = b where A is a symmetric, large and sparse matrix. The ILDL ^T< (p) factorization (p = 1,2,3, …) determines the density of the lower triangular matrix L selecting the p largest off-diagonal entries of each column during the Gaussian elimination process. This selection may be computationally expensive, but the effectiveness of the preconditioner allows us to choose very low-density factors to reduce both work time and storage requirements. This incomplete factorization can be performed reliably on H-matrices. When A is a positive definite matrix, but not an H-matrix, one can perform an incomplete factorization if positive off-diagonal entries are removed or reduced and diagonally compensated. Numerical results for a variety of problems and comparisons with other incomplete factorizations are presented. Received: August 2002 / Accepted: December 2002 RID="*" ID="*"This work was supported by the Spanish grant BFM 2001-2641.     

Asian-American cultural identity and attitudes toward mental health services.

557 Asian-American students (263 Chinese Americans, 185 Japanese Americans, and 109 Korean Americans) completed a survey consisting of a demographic questionnaire, a modified version of the Suinn-Lew Asia Self-Identity Acculturation Scale, and the Attitudes Toward Seeking Professional Psychological Help Scale (ATSPHS). A 3?×?2?×?2 multivariate analysis with main effects of ethnicity, gender, and level of acculturation and the 4 subscales of the ATSPHS as the dependent variables resulted in a significant F value for acculturation effect and nonsignificant F values for all other main and interaction effects. Regardless of ethnicity and gender, the most acculturated students were: (a) most likely to recognize personal need for professional psychological help, (b) most tolerant of the stigma associated with psychological help, and (c) most open to discussing their problems with a psychologist. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Endemic goiter in school children of Salta Province, Argentina

The Province of Salta, located in the northwest of Argentina, showed severe endemic goiter-cretinism. The purpose of our work, therefore, was to evaluate the results of the iodized salt prophylaxis measure implemented since 1963. In 1980-1981 the prevalence of goiter was determined in 16,935 school children whose ages ranged from four to 15 years. The urinary iodine/creatinine index was also determined in a subsample of 401 children. Findings revealed that the goiter prevalence in the Province was 16.1%. In 10 Departments of the Province, those with greater socioeconomic development and denser population, the prevalences found were below 10%, limit established as endemic. In the remaining 13 Departments, especially in those less developed--where mountainous regions make their access difficult and hence, their populations consume non-iodized salt obtained from natural salt basins--values exceeded this limit. The average ioduria was 104.0 micrograms I/g Cr, with 4.5% presenting values below 25 micrograms. After 20 years of prophylaxis, endemic goiter has therefore been partially eradicated. It is suggested, however, that consumption of iodized salt and, even the supply of iodized oil in those areas where prevalence is high, be recommended.     

Asian-American acculturation, severity of concerns, and willingness to see a counselor.

Asian Americans at a major West Coast university were surveyed to determine how severe each of 24 problems was for them and to assess their willingness to see a counselor for each problem. Factor analysis reduced the 24 problems to 8 areas of concern. A repeated measures analysis of variance (ANOVA) revealed that severity ratings for the 8 concerns were related to acculturation and ethnicity. With severity ratings as covariates, a repeated measures analysis of covariance (ANCOVA) was computed for willingness to see a counselor ratings. Willingness to see a counselor was found to be related to both acculturation and gender across all 8 concerns. Women expressed greater willingness to see the counselor than did men and low-medium acculturated students expressed greater willingness to see a counselor than did high-acculturated students. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Nanorod-assembled spinel Li1.05Mn1.95O4 rods with a central tunnel along the rod-axis for high rate capability of rechargeable lithium-ion batteries

Nanorod-assembled spinel Li_1.05Mn_1.95O₄ rods with a central tunnel along the rod-axis were synthesized using highly crystalline β-MnO₂ rods as self-templates. The synthesized spinel Li_1.05Mn_1.95O₄ is an assembly of several single crystal-like nanorods with an average diameter and length of 100 and 400 nm, respectively, which was determined by microstructural Rietveld refinement using the synchrotron powder XRD data. Galvanostatic battery testing showed that central-tunneled and nanorod-assembled Li_1.05Mn_1.95O₄ rods have a high charge storage capacity at high current densities in comparison with those of the spinel rods without a tunnel structure and commercial powders. Moreover, a capacity retention value of ∼81% was observed at the end of 100 cycles at a current of 250 mAh g⁻¹.