Effect of testosterone on T cell-mediated immunity in two species of Mediterranean lacertid lizards

One of the primary assumptions of the immunocompetence handicap hypothesis is that testosterone has an immunosuppressive effect, but conflicting results have been reported in a variety of bird species concerning the effect of testosterone on the humoral and the T cell-mediated components of the immune system. The T cell-mediated component of the immune system is particularly important during the breeding season, because the likelihood of injury during sexual competition is high and T cell-mediated immunity is essential for healing wounds and resisting infection. In this study we examined the effect of experimentally increased levels of testosterone during breeding season on T cell-mediated immunity in male lizards of two Mediterranean lacertid species, Psammodromus algirus and Acanthodactylus erythrurus. The hormonal treatment significantly increased testosterone of the experimental individuals. T cell-mediated responses to phytohemagglutinin stimulation were significantly suppressed in testosterone-treated males of both species. Furthermore, there was a significant negative relationship between individual variability in T cell-mediated responsiveness and plasma testosterone concentration. The present study is the first to demonstrate testosterone-induced suppression of T cell-mediated immunity in lizards.     

Synthesis and biological evaluation of paclitaxel-thiocolchicine hybrids

The bifunctional taxoid-colchicinoid hybrids 6-8 were synthesized and evaluated in assays of cytotoxicity and tubulin assembly/disassembly. All compounds showed a high degree of cytotoxicity, but, while 6 and 7 behaved as bifunctional tubulin binders not unlike an equimolecular mixture of taxol and thiocolchicine, 8 was surprisingly devoid of tubulin activity, acting on a distinct and yet to identify molecular target.     

An innovative application of the "flexible" GRID/PCA computational method: study of differences in selectivity between PGAs from Escherichia coli and a Providentia rettgeri mutant

The original GRID/PCA technique was adapted for the development of a tool potentially useful for the plan of a research strategy in rational enzyme design. The use of the MOVE directive of GRID made it possible to partially take into account protein flexibility, and the multivariate analysis was used as an instrument for focusing only on relevant information related to the differences in enzyme substrate selectivities. The comparison of two different penicillin G acylases, from Escherichia coli and from Providentia rettgeri, was used as a case study; these enzymes are very similar and their reported selectivities differ only for a couple of mutations around the active site. The "flexible" GRID/PCA method was able to correctly predict the observed selectivity differences caused not only by mutations of residues of the active site but also by long range effects on substrate selectivity due to sequence mutations on residues not directly involved in substrate recognition.     

Cancer of the endometrium: current aspects of diagnostics and treatment

Background  

Endometrial cancer represents a tumor entity with a great variation in its incidence throughout the world (range 1 to 25). This suggests enormous possibilities of cancer prevention due to the fact that the incidence is very much endocrine-related, chiefly with obesity, and thus most frequent in the developed world. As far as treatment is concerned, it is generally accepted that surgery represents the first choice of treatment. However, several recommendations seem reasonable especially with lymphadenectomy, even though they are not based on evidence. All high-risk cases are generally recommended for radiotherapy.     

The flavoprotein MrsD catalyzes the oxidative decarboxylation reaction involved in formation of the peptidoglycan biosynthesis inhibitor mersacidin

The lantibiotic mersacidin inhibits peptidoglycan biosynthesis by binding to the peptidoglycan precursor lipid II. Mersacidin contains an unsaturated thioether bridge, which is proposed to be synthesized by posttranslational modifications of threonine residue +15 and the COOH-terminal cysteine residue of the mersacidin precursor peptide MrsA. We show that the flavoprotein MrsD catalyzes the oxidative decarboxylation of the COOH-terminal cysteine residue of MrsA to an aminoenethiol residue. MrsD belongs to the recently described family of homo-oligomeric flavin-containing Cys decarboxylases (i.e., the HFCD protein family). Members of this protein family include the bacterial Dfp proteins (which are involved in coenzyme A biosynthesis), eukaryotic salt tolerance proteins, and further oxidative decarboxylases such as EpiD. In contrast to EpiD and Dfp, MrsD is a FAD and not an FMN-dependent flavoprotein. HFCD enzymes are characterized by a conserved His residue which is part of the active site. Exchange of this His residue for Asn led to inactivation of MrsD. The lantibiotic-synthesizing enzymes EpiD and MrsD have different substrate specificities.     

Active site residues of cyclophilin A are crucial for its signaling activity via CD147

Cyclophilin A (CyPA), a ubiquitously distributed intracellular protein, is a peptidylprolyl cis-trans-isomerase and the major target of the potent immunosuppressive drug cyclosporin A. Although expressed predominantly as an intracellular molecule, CyPA is secreted by cells in response to inflammatory stimuli and is a potent neutrophil and eosinophil chemoattractant in vitro and in vivo. The mechanisms underlying CyPA-mediated signaling and chemotaxis are unknown. Here, we identified CD147 as a cell surface receptor for CyPA and demonstrated that CD147 is an essential component in the CyPA-initiated signaling cascade that culminates in ERK activation. Both signaling and chemotactic activities of CyPA depended also on the presence of heparans, which served as primary binding sites for CyPA on target cells. The proline 180 and glycine 181 residues in the extracellular domain of CD147 were critical for signaling and chemotactic activities mediated by CD147. Also crucial were active site residues of CyPA, because rotamase-defective CyPA mutants failed to initiate signaling events. These results establish cyclophilins as natural ligands for CD147 and suggest an unusual, rotamase-dependent mechanism of signaling.     

Marked differences in unilateral isolated retinoblastomas from young and older children studied by comparative genomic hybridization

Although it is established that the loss of function of both alleles of the RB1 gene is a prerequisite for the development of retinoblastoma, little is known about the genetic events that are required for tumor progression. We used comparative genomic hybridization (CGH) to search for DNA copy number changes in isolated unilateral retinoblastomas. From a series of 66 patients with retinoblastomas with somatic mutations in both RB1 alleles, tumor samples from 13 children with the youngest (2.0-9.8 months) and 13 with the oldest (36.2-84.1 months) age at operation were studied. Loss at 13q14, the location of RB1, was demonstrated in two tumors only. Recurring chromosome imbalances included gains at 6p (11/26), 1q (10/26), 2p (4/26), and 17q (4/26), gains of the entire chromosome 19 (3/26), and losses at 16q (9/26). A commonly gained region at 1q32 was identified. Increased dosage of GAC1, a candidate oncogene located in 1q32, was found in two of four tumors by Southern blot analysis. Comparison of the CGH findings revealed that retinoblastomas from children with an older age at operation showed significantly more frequent (13/13 cases vs 4/13 cases; P = 0.0005) and more complex genetic abnormalities (median, 5 changes/abnormal tumor vs median, 1.5 changes/abnormal tumor; P = 0.003) than retinoblastomas from children with a young age at operation. Gains at 1q, 2p, 17q, of the entire chromosome 19 and losses of 16q were restricted to the older age group. Our results suggest that the progression of retinoblastomas from older patients follows mutational pathways different from those of younger patients.     

Study on immunobiology in endoparasites of public health interest: echinococcosis-hydatidosis

Cystic echinococcosis caused by Echinococcus granulosus is one of the most widespread zoonoses in the Mediterranean, endemic in some regions such as Sardinia. Some aspects of the research conducted in this area are briefly reviewed for an integrated analysis of both epidemiological and immunobiological knowledge, gained from field observations and experimental studies. Data on epidemiology in intermediate hosts, immunological assessment of exposure in humans, immune response and Th1/Th2 polarization in secondary experimental hydatidosis, kinetics of response in definitive host and cytokine production in experimental models are briefly reported. They confirm the usefulness of an immunobiological approach both in intermediate and definitive hosts and their potential in prevention, monitoring and control of E/H.     

Effect of hyaluronic acid on human chondrocyte cell lines from articular cartilage

The effects of hyaluronic acid (HA) derivative on the proliferation and metabolism of human chondrocytes were examined. Cells were obtained from cartilage from metatarsal phalangeal joints of 20 adult humans (aged 22-63) and from femoral knee condyles of 10 subjects (aged 22-77). Chondrocytes isolated by collagenase/Dnase digestion were cultured with addition of different doses of HA for 4 weeks. Morphological studies demonstrated that HA enhanced the adhesion of cells to substrate; HA-treated chondrocytes proliferated better than chondrocytes cultured in HA-free medium. This study shows that HA improves in vitro substrate adhesion ability and proliferative activity of human cartilage cells and that the response to the treatment varies on an individual basis.