Zeniplatin in patients with advanced ovarian cancer, a phase II study with a third generation platinum complex

25 patients with residual or recurrent ovarian cancer were treated with the new platinum complex zeniplatin (CL 286,558) and 23 patients were evaluable for response. Responses were achieved in 4 patients, 1 complete and 3 partial remissions (16%). 7 patients had stable disease and 12 patients had tumour progression. At a median follow-up of 12 months, the median progression-free survival in responding patients was 11 months and overall survival 81%. The median overall survival of progressive patients amounted to 9 months, indicating the advanced stage of disease in most patients. Renal function was monitored by isotope clearance studies. There was no significant change in effective renal plasma flow (ERPF) or glomerular filtration rate (GFR) in 10 patients who completed six cycles of treatment. 1 patient with a marginal creatinine clearance at baseline suffered from sudden and severe renal failure during the first cycle. Zeniplatin may be active in relapsing, platinum-pretreated patients, and has no direct effects on renal function as measured by isotope clearance. Despite these findings, occasional nephrotoxicity may occur in patients with compromised kidney function, even with prophylactic hydration, and thus limit the application of this new analogue

Risk factors for gastrointestinal bleeding in patients with gastrointestinal cancer using edoxaban

Background In the Hokusai VTE Cancer study, the risk of major bleeding was 2.9% higher in the edoxaban group compared with the dalteparin group, mainly due to more gastrointestinal bleedings in patients with gastrointestinal cancer. The identification of risk factors for gastrointestinal bleeding may help to guide the use of DOACs in these patients. Objectives To evaluate risk factors for gastrointestinal bleeding in patients with gastrointestinal cancer receiving edoxaban. Patients/Methods In this nested case-control study in patients with gastrointestinal cancer randomized to edoxaban in the Hokusai VTE Cancer study, cases (patients with clinically relevant gastrointestinal bleeding during treatment) were randomly matched to three controls (patients who had no gastrointestinal bleeding). Data for the 4-week period prior to bleeding were retrospectively collected. Odds ratios (ORs) were calculated in a crude conditional logistic regression model and a multivariable model adjusted for age, sex, and cancer type. Results Twenty-four cases and 64 matched controls were included. In the multivariable analysis, advanced cancer, defined as regionally advanced or metastatic cancer (OR 3.6, 95% CI 1.01-12.6) and low hemoglobin levels (OR 4.8, 95% CI 1.5-16.0) were significantly associated with bleeding. There was no significant difference in patients with resected tumors (OR 0.4, 95% CI 0.1-1.4), or in patients on chemotherapy (OR 1.3, 95% CI 0.5-3.5). Conclusion Advanced cancer and low hemoglobin levels were associated with an increased risk of gastrointestinal bleeding in patients with gastrointestinal cancer receiving edoxaban. We were unable to identify other risk factors, mainly due to limited statistical power.Thrombosis and Hemostasi

Design and synthesis of discontinuous protein binding site mimics of HIV gp120

Essentially all cellular processes are mediated by protein-protein interactions and detailed knowledge about these interactions can aid in determining biological functions or provide opportunities for the treatment of human disease. Extensive research has been performed on the development of modulators of protein-protein interactions, since these molecules could provide better understanding of the mechanisms of molecular recognition, lead to the identification of drug targets or provide access to novel therapeutics. Peptide-based mimics of protein binding sites are promising candidates for this purpose. Despite the progress that has been made in the field of protein mimicry and the increasing understanding of protein-protein interactions, the development of molecules that can modulate these interactions remains a challenging task because of the complex nature of protein binding sites. Protein-protein interaction sites often consist of discontinuous epitopes. An important example of such an interaction is the CD4 binding site of HIV gp120. Since gp120 plays a central role in the ability of HIV to enter cells, it is an interesting target for vaccine research. Therefore, in this thesis the development of a fast and reliable method for the synthesis of collections of discontinuous epitope mimics is described. The method comprises the conjugation of three different cyclic peptides, representing the epitopes, to a scaffold molecule, using the copper(I)-catalyzed alkyne-azide cycloaddition reaction. The main characteristic of our method is the rapid generation in a single experiment of a mixture of multiple discontinuous epitope constructs. Thus, a diversity of combinations of cyclic peptides on a scaffold molecule is accessible in a reproducible manner. These different constructs can be conveniently separated by preparative HPLC and characterized with mass spectrometry. The mixture and the individual constructs were tested for CD4-binding affinity with ELISA for evaluation of their ability to act as gp120 mimics. This synthetic procedure provides rapid access to a diversity sophisticated peptide biomolecular constructs. Moreover, the synthesis and activity screening of multiple products in one approach enhances the probability to rapidly generate a starting point for developing synthetic vaccines derived from gp120 or neutralizing antibodies targeting CD

A combinatorial approach toward smart libraries of discontinuous epitopes of HIV gp120 on a TAC synthetic scaffold

We describe rapid and convenient access to smart libraries of protein surface discontinuous epitope mimics. Up to three different cyclic peptides, representing discontinuous epitopes in HIV-gp120, were conjugated to a triazacyclophane scaffold molecule via CuAAC. In this way protein mimics for use as synthetic vaccines and beyond will become available

ANALYSIS OF THE REDUCTION OF HYDROGEN-INDUCED INFRARED LOSS INCREASES IN FLUORINE-DOPED PCVD SILICA FIBRE PREFORMS

Les spectres de transmission d'infrarouges en fonction du rayon dans les préformes de silice PCVD, dopées au fluor, à structure étagée, avec diffusion d'hydrogène ont révélé une diminution marquée et à corrélation mutuelle de l'absorption de deux bandes OH présentes à 3710 and 3590 cm-1. Cette diminution est apparemment associée à un accroissement de la teneur en fluor du verre. Ces bandes sont attribuées aux deux vibrations d'étirage O-H dans une paire silanol à pont d'hydrogène asymétrique. Les emplacements "défectueux" de la structure réticulée de la silice, où on trouve des anneaux petits mais réguliers de liaisons Si-O, conviennent pour générer les paires silanol asymétriques. Etant donné que l'addition de fluor se produit de manière préférentielle aux emplacements "défectueux'', les pertes d'infrarouges diminuent à mesure que la teneur en fluor s'accroît.Infrared transmission spectra as a function of the radius in hydrogen-diffused, multiple-step fluorine-doped PCVD silica preforms showed a marked and mutually coupled decrease in the absorption of two OH bands present at 3710 and 3590 cm-1. This decrease is apparently correlated with an increasing fluorine content in the glass. These bands are assigned to the two O-H stretching vibrations in an asymmetric hydrogen-bridged silanol pair. "Defect" sites in the silica network structure consisting of small but regular rings of Si-O bonds are suitable for generating the asymmetric silanol pairs. As the fluorine addition occurs preferentially at the "defect" positions, the infrared loss associated with these bands decreases for increasing fluorine content

Mirror image supramolecular helical tapes formed by the enantiomeric-depsipeptide derivatives of the amyloidogenic peptide amylin(20–29)

Factors that determine the chirality of supramolecular helical tapes formed by a backbone-modified amylin(20–29) depsipeptide and inverso-depsipeptide, were studied by Fourier transform infrared spectroscopy, circular dichroism and transmission electron microscopy. Although β-sheet propensity was absent in both peptides, it was found that the l-depsipeptide formed left-handed and the enantiomeric d-depsipeptide right-handed helical tapes. Moreover, the backbone-modified depsipeptides, showed a certain degree of cross-recognition between both enantiomers, which might have implications in designing amyloid formation inhibitors

Transformation of the amyloidogenic peptide amylin(20–29) into its corresponding peptoid and retropeptoid: Access to both an amyloid inhibitor and template for self-assembled supramolecular tapes

The highly amyloidogenic peptide sequence of amylin(20–29) was transformed into its corresponding peptoid and retropeptoid sequences to design a novel class of β-sheet breaker peptides as amyloid inhibitors. This report describes the synthesis of the chiral peptoid building block of l-isoleucine, the solid phase synthesis of the peptoid and retropeptoid sequences of amylin(20–29), and the structural analysis of these amylin derivatives in solution by infrared spectroscopy, circular dichroism, and transmission electron microscopy. It was found that the peptoid sequence did not form amyloid fibrils or any other secondary structures and was able to inhibit amyloid formation of native amylin(20–29). Although the retropeptoid did not form amyloid fibrils it had only modest amyloid inhibitor properties since supramolecular tapes were formed

Higher number of pentosidine cross-links after ribose treatment does not alter tissue stiffness of cancellous bone

Abstracts of ECTS 2012, 39th Annual Congress, Stockholm, Sweden (May 19-23, 2010) : ECTS 2012, 39th Annual Congress