Parallel conduction of the phase I preventive and therapeutic trials based on the Tat vaccine candidate.

The native HIV-1 Tat protein was chosen as vaccine candidate for phase I clinical trials in both uninfected (ClinicalTrials.gov identifier: NCT00529698) and infected volunteers (ClinicalTrials.gov identifier: NCT00505401). The rationale was based on the role of Tat in the natural infection and AIDS pathogenesis, on the association of Tat-specific immune responses with the asymptomatic stage and slow-progression rate as well as on its sequence conservation among HIV clades (http://www.hiv1tat-vaccines.info/). The parallel conduction in the same clinical centers of randomized, double blind, placebo-controlled phase I studies both in healthy, immunologically competent adults and in HIV-infected, clinically asymptomatic, individuals represents a unique occasion to compare the vaccine-induced immune response in both the preventive and therapeutic setting. In both studies, the same lot of the native Tat protein was administered 5 times, every four weeks, subcute (SC) with alum adjuvant or intradermic (ID), in the absence of adjuvant, at 7.5 microg, 15 microg or 30 microg doses, respectively. The primary and secondary endpoints of these studies were the safety and immunogenicity of the vaccine candidate, respectively. The study lasted 52 weeks and monitoring was conducted for on additional 3 years. The results of both studies indicated that the Tat vaccine is safe and well tolerated both locally and systemically and it is highly immunogenic at all the dosages and by both routes of administration. Vaccination with Tat induced a balanced immune response in uninfected and infected individuals. In particular, therapeutic immunization induced functional antibodies and partially reverted the marked Th1 polarization of anti-Tat immunity seen in natural infection, and elicited a more balanced Th1/Th2 immune response. Further, the number of CD4 T cells correlated positively with anti-Tat antibody titers. Based on these results, a phase II study is ongoing in infected drug-treated individuals (http://www.hiv1tat-vaccines.info/).

C-Raf antagonizes apoptosis induced by IFN-alpha in human lung cancer cells by phosphorylation and increase of the intracellular content of elongation factor 1A.

Interferon alpha (IFNalpha) induces both apoptosis and a counteracting epidermal growth factor Erk-dependent survival response in cancer cells. In this report, IFNalpha increased eukaryotic elongation factor 1A (eEF-1A) protein expression by inhibition of eEF-1A degradation via a proteasome-dependent pathway. The reduction of the expression level of eEF-1A by RNA interference enhanced the apoptosis induced by IFNalpha on the same cells. Moreover, IFNalpha induced the phosphorylation of both serine and threonine in eEF-1A. These effects were paralleled by an increased co-immunoprecipitation and colocalization of eEF-1A with C-Raf. The suppression of C-Raf kinase activity with the inhibitor BAY 43-9006 completely antagonized the increase of both eEF-1A phosphorylation and expression and of C-Raf/eEF-1A colocalization induced by IFNalpha and enhanced apoptosis and eEF-1A ubiquitination. Cell transfection with the mutated K48R ubiquitin increased EF-1A expression and desensitized tumor cells to the modulating effects of IFNalpha. The dynamic simulation of 3Dstructure of eEF-1A identified putative serine and threonine phosphorylation sites. In conclusion, the interaction between eEF-1A and C-Raf increases eEF-1A stability and induces a survival activity.

The translation elongation factor 1A in tumorigenesis, signal transduction and apoptosis: review article.

An increasing number of evidences suggest the involvement of the eukaryotic elongation factor 1A, a core component of the protein synthesis machinery, at the onset of cell transformation. In fact, eEF1A is shown to be up-regulated in cell death; moreover, it seems to be involved in the regulation of ubiquitin-mediated protein degradation. In addition, eEF1A undergoes several post-translational modifications, mainly phosphorylation and methylation, that generally influence the activity of the protein. This article summarizes the present knowledges on the several extra-translational roles of eEF1A also in order to understand as the protein synthesis regulatory mechanisms could offer tools for cancer intervention.

Quality of life and peripheral lymphedema.

Evaluation of the health-related quality of life (QOL) is becoming commonplace, seeking to provide information about the everyday well-being of a patient. This work examined the QOL of 23 consecutive patients with lymphedema of the upper or lower extremities. Five were men and the other eighteen were women. Their ages ranged from 19 to 74 years (mean 48.3). After clinical examination, and with informed consent of each patient, they were assessed by a psychologist and submitted to a QOL test (SF-36). For controls, twenty-three women and five men with age range of 28 to 66 years (mean 47) were similarly evaluated. The results showed the lymphedema group had a statistically significantly reduced QOL in both physical and mental health as well as social interaction.

Bioactive constituents of the bark of Parkia biglobosa.

In the frame of a systematic analysis of African plants used for the 'cure salée', from the bark of Parkia biglobosa, a long-chain ester of trans-ferulic acid (1) has been isolated together with an unseparable mixture of long-chain cis-ferulates (2a-e). In addition, lupeol, 4-O-methyl-epi-gallocatechin, epi-gallocatechin, epi-catechin 3-O-gallate, and epi-gallocatechin 3-O-gallate were isolated.

Hot heads and cold brains. Aristotle, Galen and the "radiator theory".

The Author examines two similar theories about the functioning of human brain as a refrigerator: Falk's and Fialkowski's (1990) and Aristotle's (IVth century b.C.). There are surprising, although fortuitous, convergences between the two, with the remarkable difference, however, that Artistotle's doctrine (later severely criticized by Galen) thinks of the brain merely as an organ for the cooling of the body's (the heart's) heat, while according to the modern radiator theory the human brain developed starting as a refrigerator of itself.