Signal transduction inhibitors as radiosensitizers

DNA double strand breaks are the pivotal cellular damage induced by ionizing radiation. A plethora of molecular and cellular processes are activated as part of the cellular stress response that result in cell cycle arrest and induction of the DNA-repair machinery to restore the damage of DNA or to activate a cell death program. However ionizing radiation also initiates signal transduction cascades that are generated at cellular sites distant from and independent of DNA-damage. These signaling processes are similar to hormone activated growth factor receptor controlled signal transduction cascades and represent interesting targets for anticancer treatment modalities combining ionizing radiation with molecular defined pharmacological compounds. Activation of these signal transduction cascades upon irradiation or upregulation of growth factor mediated pathways due to oncogene-transformation often contribute to an acquired or inherent treatment resistance in malignant cells. Therefore pharmacological compounds inhibiting specific key-entities of these signal transduction cascades potentially sensitize for radiation induced cell death. Here we describe current preclinical concepts of combined treatment strategies with locoregional-applied ionizing radiation and molecular defined signal transduction inhibitors to overcome a high treatment threshold in tumor cells.     

Comparison of efficacy and immunogenicity of original versus current botulinum toxin in cervical dystonia

The authors compared 130 patients treated for cervical dystonia with original botulinum toxin (BTX) type A (Botox; Allergan, Inc., Irvine, CA), 42 of whom were exposed only to the original BTX type A used before 1998 (25 ng protein/100 units), and 119 treated only with the current BTX type A (5 ng of protein/100 units). Blocking antibodies were detected in 4 of 42 (9.5%) patients treated only with original BTX type A but in none of the 119 patients treated exclusively with current BTX type A (p < 0.004). The current preparation decreased the risk of antibody formation by a factor of six. The authors conclude that the low risk of antibody formation after current BTX type A treatment is related to lower protein load.     

Impact of the agr quorum-sensing system on adherence to polystyrene in Staphylococcus aureus

Biofilm formation by Staphylococcus aureus is a serious problem in nosocomial infections. There are great differences in the capacity of S. aureus to express biofilms, but the reasons are unknown. In all, 105 S. aureus strains were tested for a correlation between the agr quorum-sensing system phenotype and the ability of S. aureus to adhere to polystyrene. Some 78% of agr-negative, but only 6% of agr-positive, strains formed a biofilm, demonstrating a profound impact of agr on biofilm formation. This result was confirmed with defined agr mutants and by inhibition of agr with quorum-sensing blockers. The observed effect was not due to differential expression of the autolysin Atl or of the exopolysaccharide polysaccharide intercellular adhesin but seemed to be caused, at least in part, by the surfactant properties of delta-toxin. The detected biofilm-enhancing effect of S. aureus quorum-sensing blockers call into question the proposed therapeutic use of such substances.     

Induction of esophageal tumors in zinc-deficient rats by single low doses of N-nitrosomethylbenzylamine (NMBA): analysis of cell proliferation, and mutations in H-ras and p53 genes

Dietary zinc deficiency in rats induces hyperplasia in the esophagus and increases N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumor incidence. Previous work showed a direct relationship between epithelial cell proliferation and esophageal tumor incidence in rats given multiple doses of NMBA. We investigated the effects of single low doses of NMBA in zinc-deficient rats since a single dose of 5.0 mg/kg was reported to be non-carcinogenic in rats. Zinc-sufficient and deficient rats received a single i.g. dose of NMBA at 0.5 or 2.0 mg/kg. At week 14, tumor incidence was 50% with 0.8 +/- 1.0 tumors/rat, and 80% with 2.2 +/- 1.9 tumors/rat, in deficient groups, D(0.5) and D(2.0), that received the lower and higher dose, respectively. In addition, two small papillomas were found in one out of eight untreated zinc-deficient rats. None of the NMBA-treated or untreated zinc- sufficient rats had any tumors. Esophageal cell proliferation, as determined by proliferating cell nuclear antigen (PCNA) immunohistochemistry, showed that, irrespective of NMBA treatment, deficient esophagi had significant increases in the number of labeled cells, the total number of cells, and the labeling index, as compared with zinc-sufficient ones. Mutations in Ha-ras and p53 genes in esophageal tumors were detected by single strand conformation polymorphism (SSCP) analysis. DNA sequencing of variant conformers revealed a point mutation (GGA-->GAA, codon 12) in Ha-ras in 4/5 (80%) and 5/8 (63%) tumors, from D(0.5) and D(2.0) rats, respectively. Three out of eight tumors from D(2.0) rats exhibited SSCP mobility shifts within p53 exons 5 and 7: two tumors (2/8, 25%) had missense mutations and the third, a silent mutation. Of the two tumors with p53 mutations, one had a double mutation (transition at codon 164, TCA-->TTA; transversion at codon 241, AGT-->TGT), and the other tumor, a transition at codon 172 (AGA-->GGA), with amino acid changes in all cases. In parallel with PCNA expression, elevated p53 expression was associated with hyperplastic and dysplastic regions, as well as with tumors, in deficient esophagi. In short, these data indicate that dietary zinc deficiency, with its associated sustained increased cell proliferation in the esophagus, can drive an otherwise non-tumorigenic dose of NMBA into a highly tumorigenic one.      

Phorbasin A: a novel diterpene from a southern australian marine sponge, Phorbas species

A southern Australian Phorbas species has yielded a novel diterpene, phorbasin A (1), possessing an unprecedented carbon skeleton. The structure for phorbasin A was determined by detailed spectroscopic analysis.     

Magnetic resonance imaging after cochlear implants

Introduction

Most cochlear implants are currently compatible with magnetic resonance imaging (MRI) up to 3?T. Nevertheless, this does not completely eliminate the risk of serious accidents. Implant displacements and other adverse events with compatible implants have been reported in the literature.

Key role of poly-gamma-DL-glutamic acid in immune evasion and virulence of Staphylococcus epidermidis

Coagulase-negative staphylococci, with the leading species Staphylococcus epidermidis, are the predominant cause of hospital-acquired infections. Treatment is especially difficult owing to biofilm formation and frequent antibiotic resistance. However, virulence mechanisms of these important opportunistic pathogens have remained poorly characterized. Here we demonstrate that S. epidermidis secretes poly-gamma-DL-glutamic acid (PGA) to facilitate growth and survival in the human host. Importantly, PGA efficiently sheltered S. epidermidis from key components of innate host defense, namely antimicrobial peptides and neutrophil phagocytosis, and was indispensable for persistence during device-related infection. Furthermore, PGA protected S. epidermidis from high salt concentration, a key feature of its natural environment, the human skin. Notably, PGA was synthesized by all tested strains of S. epidermidis and a series of closely related coagulase-negative staphylococci, most of which are opportunistic pathogens. Our study presents important novel biological functions for PGA and indicates that PGA represents an excellent target for therapeutic maneuvers aimed at treating disease caused by S. epidermidis and related staphylococci.