Bombesin peptide antagonist for target-selective delivery of liposomal doxorubicin on cancer cells

Purpose: This study addresses novel peptide modified liposomal doxorubicin to specifically target tissues overexpressing bombesin (BN) receptors. Methods: DOTA-(AEEA)2-peptides containing the [7–14]bombesin and the new BN-AA1 sequence have been synthesized to compare their binding properties and in serum stabilities. The amphiphilic peptide derivative (MonYBN- AA1) containing BN-AA1, a hydrophobic moiety, polyethylenglycole (PEG), and diethylenetriaminepentaacetate (DTPA), has been synthesized. Liposomes have been obtained by mixing of MonY-BN-AA1 with 1,2-distearoylsn-glycero-3-phosphocholine (DSPC). Results: Both 111In labeled peptide derivatives present nanomolar Kd to PC-3 cells. 177Lu labeled peptide DOTA- (AEEA)2-BN-AA1 is very stable (half-life 414.1 h), while DOTA-(AEEA)2-BN, shows a half-life of 15.5 h. In vivo studies on the therapeutic efficacy of DSPC/MonY-BN-AA1/Dox in comparison to DSPC/MonY-BN/Dox, were performed in PC-3 xenograft bearing mice. Both formulations showed similar tumor growth inhibition (TGI) compared to control animals treated with non-targeted DSPC/Dox liposomes or saline solution. For DSPC/MonY-BN-AA1/Dox the maximum effect was observed 19 days after treatment. Conclusions: DSPC/MonY-BN-AA1/Dox nanovectors confirm the ability to selectively target and provide therapeutic efficacy in mice. The lack of receptor activation and possible acute biological side effects provided by using the AA1 antagonist bombesin sequence should provide safe working conditions for further development of this class of drug delivery vehicles

Guidelines and Recommendations on the Use of Higher OrderFinite Elements for Bending Analysis of Plates

This paper compares and evaluates various plate finite elements to analyse the static response of thick and thin plates subjected to different loading and boundary conditions. Plate elements are based on different assumptions for the displacement distribution along the thickness direction. Classical (Kirchhoff and Reissner-Mindlin), refined (Reddy and Kant), and other higher-order displacement fields are implemented up to fourth-order expansion. The Unified Formulation UF by the first author is used to derive finite element matrices in terms of fundamental nuclei which consist of 3 × 3 arrays. The MITC4 shear-locking free type formulation is used for the FE approximation. Accuracy of a given plate element is established in terms of the error vs. thickness-to-length parameter. A significant number of finite elements for plates are implemented and compared using displacement and stress variables for various plate problems. Reduced models that are able to detect the 3D solution are built and a Best Plate Diagram (BPD) is introduced to give guidelines for the construction of plate theories based on a given accuracy and number of terms. It is concluded that the UF is a valuable tool to establish, for a given plate problem, the most accurate FE able to furnish results within a certain accuracy range. This allows us to obtain guidelines and recommendations in building refined elements in the bending analysis of plates for various geometries, loadings, and boundary conditions

Mechanical properties of MWPECVD diamond coatings on Si substrate via nanoindentation

The mechanical properties of polycrystalline diamond coatings with thickness varying from 0.92 to 44.65 μm have been analysed. The tested samples have been grown on silicon substrates via microwave plasma enhanced chemical vapour deposition from highly diluted gas mixtures CH4–H2 (1% CH4 in H2). Reliable hardness and elastic modulus values have been assessed on lightly polished surface of polycrystalline diamond films. The effect of the coating thickness on mechanical, morphological and chemical-structural properties is presented and discussed. In particular, the hardness increases from a value of about 52 to 95 GPa and the elastic modulus from 438 to 768 GPa by varying the coating thickness from 0.92 to 4.85 μm, while the values closer to those of natural diamond (H=103 GPa and E=1200 GPa) are reached for thicker films (N5 μm). Additionally, the different thickness of the diamond coatings permits to select the significance of results and to highlight when the soft silicon substrate may affect the measured mechanical data. Thus, the nanoindentation experiments were made within the range from 0.65% to 10% of the film thickness by varying the maximum load from 3 to 80 mN. © 2010 Elsevier B.V. All rights reserve

Using death to one's advantage: HIV modulation of apoptosis

Infection by human immunodeficiency virus (HIV) is associated with an early immune dysfunction and progressive destruction of CD4+ T lymphocytes. This progressive disappearance of T cells leads to a lack of immune control of HIV replication and to the development of immune deficiency resulting in the increased occurrence of opportunistic infections associated with acquired immune deficiency syndrome (AIDS). The HIV-induced, premature destruction of lymphocytes is associated with the continuous production of HIV viral proteins that modulate apoptotic pathways. The viral proteins, such as Tat, Env, and Nef, are associated with chronic immune activation and the continuous induction of apoptotic factors. Viral protein expression predisposes lymphocytes, particularly CD4+ T cells, CD8+ T cells, and antigen-presenting cells, to evolve into effectors of apoptosis and as a result, to lead to the destruction of healthy, non-infected T cells. Tat and Nef, along with Vpu, can also protect HIV-infected cells from apoptosis by increasing anti-apoptotic proteins and down- regulating cell surface receptors recognized by immune system cells. This review will discuss the validity of the apoptosis hypothesis in HIV disease and the potential mechanism(s) that HIV proteins perform in the progressive T cell depletion observed in AIDS pathogenesis. Originally published Leukemia, Vol. 15, No. 3, Mar 200

Optimisation du processus de texturation des surfaces métalliques par faisceau laser

Le processus de texturation par laser représente la réalisation de motifs micro/macro géométrique, plus ou moins réguliers sur une surface métallique, à l'aide d'un faisceau d'énergie concentré dans un spot très fin. Obtenir des indicateurs de performances optimaux, oblige à étudier et comprendre les interactions physico-chimiques apparues dans la zone d'impact faisceau laser - matière. Cet article présente l'étude expérimentale et numérique sur le processus de texturation par laser pulsé de l'alliage de titane TA6V. Dans une première partie l'influence des paramètres opératoires sur les indicateurs des performances a été quantifiée par la méthodologie des plans des expériences. En analysant les résultats on a observé que la productivité et la qualité de la surface texturée dépend de l'énergie et de la fréquence des impulsions. Afin de déterminer les corrélations entre les paramètres opératoires et les fonctions objectifs, des modèles empiriques ont été établis

HIV-1 envelope, integrins and co-receptor use in mucosal transmission of HIV

It is well established that HIV-1 infection typically involves an interaction between the viral envelope protein gp120/41 and the CD4 molecule followed by a second interaction with a chemokine receptor, usually CCR5 or CXCR4. In the early stages of an HIV-1 infection CCR5 using viruses (R5 viruses) predominate. In some viral subtypes there is a propensity to switch to CXCR4 usage (X4 viruses). The receptor switch occurs in ~ 40% of the infected individuals and is associated with faster disease progression. This holds for subtypes B and D, but occurs less frequently in subtypes A and C. There are several hypotheses to explain the preferential transmission of R5 viruses and the mechanisms that lead to switching of co-receptor usage; however, there is no definitive explanation for either. One important consideration regarding transmission is that signaling by R5 gp120 may facilitate transmission of R5 viruses by inducing a permissive environment for HIV replication. In the case of sexual transmission, infection by HIV requires the virus to breach the mucosal barrier to gain access to the immune cell targets that it infects; however, the immediate events that follow HIV exposure at genital mucosal sites are not well understood. Upon transmission, the HIV quasispecies that is replicating in an infected donor contracts through a “genetic bottleneck”, and often infection results from a single infectious event. Many details surrounding this initial infection remain unresolved. In mucosal tissues, CD4+ T cells express high levels of CCR5, and a subset of these CD4+/CCR5high cells express the integrin α4β7, the gut homing receptor. CD4+/CCR5high/ α4β7high T cells are highly susceptible to infection by HIV-1 and are ideal targets for an efficient productive infection at the point of transmission. In this context we have demonstrated that the HIV-1 envelope protein gp120 binds to α4β7 on CD4+ T cells. On CD4+/CCR5high/ α4β7high T cells, α4β7 is closely associated with CD4 and CCR5. Furthermore, α4β7 is ~3 times the size of CD4 on the cell surface, that makes it a prominent receptor for an efficient virus capture. gp120-α4β7 interactions mediate the activation of the adhesion-associated integrin LFA-1. LFA-1 facilitates the formation of virological synapses and cell-to-cell spread of HIV-1. gp120 binding to α4β7 is mediated by a tripeptide located in the V1/V2 domain of gp120. Of note, the V1/V2 domain of gp120 has been linked to variations in transmission fitness among viral isolates raising the intriguing possibility that gp120-α4β7 interactions may be linked to transmission fitness. Although many details remain unresolved, we hypothesize that gp120-α4β7 interactions play an important role in the very early events following sexual transmission of HIV and may have important implication in the design of vaccine strategies for the prevention of acquisition of HIV infectio

HIV gp120 Induces, NF-κB Dependent, HIV Replication that Requires Procaspase 8

HIV envelope glycoprotein gp120 causes cellular activation resulting in anergy, apoptosis, proinflammatory cytokine production, and through an unknown mechanism, enhanced HIV replication.We describe that the signals which promote apoptosis are also responsible for the enhanced HIV replication. Specifically, we demonstrate that the caspase 8 cleavage fragment Caspase8p43, activates p50/p65 Nuclear Factor kappaB (NF-kappaB), in a manner which is inhibited by dominant negative IkappaBalpha. This caspase 8 dependent NF-kappaB activation occurs following stimulation with gp120, TNF, or CD3/CD28 crosslinking, but these treatments do not activate NF-kappaB in cells deficient in caspase 8. The Casp8p43 cleavage fragment also transactivates the HIV LTR through NF-kappaB, and the absence of caspase 8 following HIV infection greatly inhibits HIV replication.Gp120 induced caspase 8 dependent NF-kappaB activation is a novel pathway of HIV replication which increases understanding of the biology of T-cell death, as well as having implications for understanding treatment and prevention of HIV infection