Localization of recognition site between transforming growth factor-beta1 (TGF-beta1) and TGF beta receptor type II: possible implications in breast cancer.

Although overexpression of TGF-beta1 protein has been demonstrated in advanced breast cancer (BC) patients, as well as in other solid tumours, the molecular mechanism of this process remains obscure. This paper proposes that a genetic/epigenetic alteration might occur in the TGF-beta1 gene, within the region coding for the recognition site with TGFbeta receptor type II, leading to a disruption of the ligand-receptor interaction and triggering the TGF-beta1 cascade-related BC progression. To establish the operational framework for this hypothesis, in the present study, this recognition site was identified by the Informational Spectrum Method (ISM) to comprise two TGF-beta1 peptides (positions 47-66 aa and 83-112 aa) and one receptor peptide at positions 112-151 aa of the extracellular domain of the receptor (TbetaRIIM). The TbetaRIIM locus was further evaluated by ISM-derived deletion analysis of the TbetaRII sequences. To provide experimental support for the proposed model, a pilot study of plasma TGF-beta1 analysis was performed in advanced BC patients (n = 8). Two commercial ELISA assays, one with specific alphaTGF-beta1 MAb (MAb) and other with TbetaRIIM as the immobilized phase, revealed pronounced differences in the pattern of plasma TGF-beta1 elevation. In MAb-profile, the TGF-beta1 increase was detected in 7 of 8 patients, whereas analogous TbetaRIIM-profile revealed the elevation in 3 of 8 patients, taking a 50% of maximal elevation as the cut-off value. These findings are consistent with the proposed aberration of TGF-beta1 ligand within the TbetaRII recognition site. Summarizing, this model system is a good starting point for further genetic studies, particularly on genetic/epigenetic alterations of sequences involved in TGF-beta1 and TbetaRIIM interaction, with putative prognostic value for breast cancer.

Design of peptide mimetics of HIV-1 gp120 for prevention and therapy of HIV disease.

It has been reported that the C-terminus of the second conserved region (C2) of the envelope glycoprotein gp120, encompassing peptide RSANFTDNAKTIIVQLNESVEIN (NTM), is important for infectivity and neutralization of the human immunodeficiency virus type 1 (HIV-1). It was also demonstrated that human natural anti-vasoactive intestinal peptide (VIP) antibodies reactive with this gp120 region play an important role in control of HIV disease progression. The bioinformatic analysis based on the time-frequency signal processing revealed non-obvious similarities between NTM and VIP. When tested against a battery of sera from 46 AIDS patients, these peptides, in spite of a significant difference in their primary structures, showed a similar reactivity profiles (r = 0.83). Presented results point out that similarity in the periodical pattern of some physicochemical properties in primary structures of peptides plays a significant role in determination of their immunological crossreactivity. Based on these findings, we propose this bioinformatic criterion be used for design of VIP/NTM peptide mimetics for prevention and treatment of HIV disease.

AIDS epidemic at the beginning of the third millennium: time for a new AIDS vaccine strategy.

Current expansion of AIDS pandemic significantly accelerates AIDS vaccine research resulting in development and clinical testing of several AIDS vaccine candidates. At the same time, available experimental and clinical data demonstrate that current AIDS vaccine strategy is unsuccessful resulting in development of inefficient and harmful vaccines. This overview briefly summarizes reported results which point out the requirement for moratorium on the current clinical trials of HIV-1 gp120/160 vaccines and urgent need for development of a new, efficient and safe AIDS vaccine strategy.

Identification of an active Chi recombinational hot spot within the HIV-1 envelope gene: consequences for development of AIDS vaccines.

Because of a sequence similarity between the HIV-1 envelope glycoprotein gp120 and the variable region of human immunoglobulins, we have suggested that the use of this protein as a vaccine component could strongly influence the host immune system, making it more vulnerable to HIV, and in the long term, accelerate disease progression in asymptomatic HIV patients. Using a chimeric primer consisting of the nucleotide sequence derived from the HIV-1 env gene coding for the second conserved region of gp120, and the highly conserved sequence derived from the human immunoglobulin gene coding for the V(H)III domain, we have identified in sera of AIDS patients HIV-1 field isolates carrying the complete and active Chi recombinational hot spot (GCTGGTGG). We have also demonstrated in vivo recombination between the HIV-1 gene coding for the central portion of the gp120 involving the V3 loop and the bacterial gene coding for the clp protease. These results strongly support and reinforce the previous contention and the serious concern that AIDS vaccine candidates carrying the HIV-1 env gene on viral and bacterial vectors, could result in the generation of new pathogens with unpredictable effects on the immune system.

Study of apoB gene signal peptide insertion/deletion polymorphism in a healthy Serbian population: no association with serum lipid levels.

The apolipoprotein B (apoB) signal peptide polymorphism was studied in unrelated healthy individuals. A total of 232 women and 222 men were analyzed separately. The relative frequencies of Del allele in women and men were 0.42 and 0.37, respectively. More heterozygous individuals were detected in comparison with other populations, using a modified silver staining method on polyacrylamide gel for visualization of Ins and Del alleles. There was no statistically significant difference in mean lipid levels adjusted for age, BMI, smoking habit and blood pressure between the three Ins/Del genotypes in both samples (ANOVA). Therefore, no differences were shown in the genotype frequency distribution throughout the lipid quartiles.