Fibronectin expression in glioblastomas promotes cell cohesion, collective invasion of basement membrane in vitro and orthotopic tumor growth in mice.

Glioblastoma multiforme (GBM) are highly invasive and angiogenic malignancies with a median survival time from diagnosis of <15 months. Previous work has revealed robust overexpression of fibronectin (FN) mRNA in GBM, although immunohistochemical staining of FN in these tumors is typically associated with the angiogenic vasculature. Here we sought to examine the expression of tumor cell FN and address its possible involvement in the invasive phenotype of GBM. We found that FN was expressed and assembled into fibrillar arrays in human tumors and in established GBM lines. Cultured cells spontaneously formed dense cellular networks and spheroid-like domes. Depletion of FN by targeted-short hairpin RNA expression disrupted matrix assembly and multicellular network organization by exerting profound effects on cell adhesion and motility. Although FN depletion enhanced persistent directional migration of single cells, it compromised collective invasion of spheroids through a laminin-rich matrix and sensitized cells to ionizing radiation. In orthotopic grafts, FN depletion significantly reduced tumor growth and angiogenesis. Together our results show that FN produced by the tumor cells has a role in GBM pathophysiology and they provide insights into the implications that targeting FN interactions may have for combating this dreaded disease.

A drug interaction study between ticlopidine and cyclosporin in heart transplant recipients.

OBJECTIVES: Previous uncontrolled studies have suggested an interaction between ticlopidine, a major antiplatelet agent, and cyclosporin in heart- and kidney-transplant recipients. The aims of this study were to examine in a randomised, double-blind fashion, the possible interaction between cyclosporin A and ticlopidine (250 mg per day) and the tolerability of this combination in heart-transplant recipients. METHODS: Twenty heart-transplant recipients were randomised into either a treated or a placebo group. Blood samples were drawn for time-course evaluation of cyclosporin blood levels over a period of 12 h, following the morning intake of cyclosporin and, for platelet aggregation studies, before and after 14 days of ticlopidine administration. Twenty four-hour urine samples were collected for 6-beta-hydroxycortisol measurements, before and after 14 days of ticlopidine. RESULTS: Although given at half the recommended daily dosage, ticlopidine significantly reduced platelet aggregation. Pharmacokinetic parameters indicate that the bioavailability of cyclosporin A was not significantly modified by ticlopidine. However, one patient in the ticlopidine group was withdrawn because of a major fall in cyclosporin blood level within 3 days of treatment. Urinary excretion of 6-beta-hydroxycortisol was augmented after treatment in the ticlopidine group compared with the placebo group, suggesting that induction of drug metabolism might have occurred. Data also show quite a large intra-individual variability in cyclosporin bioavailability in the placebo group, suggesting that poor absorption of the drug formulation and/or poor compliance might have contributed to the decreased cyclosporin blood levels in the patient withdrawn from this study and in previous uncontrolled studies. CONCLUSION: Cyclosporin bioavailability was not clearly modified by a half dosage of ticlopidine in this study. We, however, recommend closely monitoring cyclosporin blood levels when prescribing ticlopidine. Further studies will be needed with new formulations of cyclosporin or when using the full dosage of ticlopidine.

Taxonomy of Leishmania. Use of isoenzymes. Suggestions for a new classification.

The authors propose a new classification for the genus Leishmania Ross, 1903 based both on the use of intrinsic and extrinsic characters and on Linnean and Adansonian methods. The type of vertebrate host makes it possible to recognize the genus group: Leishmania designates Kinetoplastida parasites of mammals. Neighbouring forms which parasite reptiles are now grouped in the genus Sauroleishmania Ranque, 1973. Characteristics of the intravectorial cycle (supra- and peri-pyloric) are used to define the subgenus group (Leishmania, Viannia Lainson and Shaw, 1987). The classification uses biochemical, particularly enzymatic, characters. Elementary taxonomic units are made up of all the strains having the same isoenzyme profile, i.e. the zymodeme. The grouping of the zymodemes is usually performed through automatic techniques which lead to bush-like trees (dendrograms) showing either simple affinities between units (phenograms) or their phyletic relationships (cladograms). The branches recognized as being stable are individualized as "zymodeme complexes". They bear the name of either the previously defined species taxa or that of a specially created one. Two examples of taxonomic constructions, phenetic and cladistic, are presented. Finally, a general classification of the genus is proposed.