Patients diagnosed with malignant glioma tumours have median survivals of 1.6 yrs and 5 months, respectively, highlighting the deadly nature of this disease. Despite aggressive multimodal treatment, patients with malignant glioma often present with secondary brain tumours at sites distal to the primary tumour mass. These secondary tumours are a consequence of renegade neoplastic cells that infiltrate the surrounding normal brain, a hallmark feature of malignant glioma. Brain fatty acid-binding protein (FABP7), which binds omega-3 docosahexaenoic acid (DHA) and omega-6 arachidonic acid (AA), is overexpressed and associated with a poor prognosis in patients with malignant glioma compared with normal brain. These data suggest that FABP7 plays an important role in gliomagenesis; however, the mechanism(s) underlying a role for FABP7 in malignant glioma has, until now, been unexplored. Here, we demonstrate that expression of FABP7 in malignant glioma cells is accompanied by increased cell migration. Consistent with our in vitro results, we show that expression of FABP7 in astrocytoma tumours is associated with sites of tumour infiltration and tumour recurrence. Furthermore, we demonstrate that the fatty-acid ligands of FABP7 affect cell migration in an FABP7-dependent manner. More specifically, DHA inhibits migration, whereas AA stimulates cell migration. Finally, we reveal that uptake and incorporation of DHA and AA in the phospholipids of malignant glioma cells is enhanced by FABP7 expression, suggesting a mechanism by which DHA and AA may affect cell migration by altering signal transduction at the cell membrane. We propose that the inherent ability of malignant glioma cells to express the radial glial marker FABP7 underlies their infiltrative capacity, allowing tumour cells to migrate long distances from the main tumour mass. We propose a model whereby FABP7 expression and relative levels of DHA and AA determine tumour infiltrative potential. Our findings provide insight into the role of FABP7 and its fatty acid ligands in controlling the migration of malignant glioma cells and point to the potential use of DHA as a natural anti-infiltrative agent in the treatment of malignant glioma. We believe that targeting FABP7-expressing cells may make a significant impact on the treatment of high grade astrocytomas. / Experimental Oncology

Three studies were conducted to determine the effects of cyclopropenoid fatty acids (CPFA) on the membrane components of livers of rainbow trout (Salmo gairdneri). In the first study, ¹⁴C-sterculic acid was administered by intraperitoneal injection into rainbow trout and the trout maintained for 72 hours. The labelled sterculic acid was found in choline phospholipids (CP) and ethanolamine phospholipids (EP). Smaller amounts of label were found in other microsomal membrane lipid components. No label was found associated with the proteins of the microsomal membrane. Phospholipase A₂ treatment of isolated CP and EP showed ¹⁴C-sterculic acid to be preferentially esterified to the 1-position of the glycerol backbone. In the second study, the cleavable bifunctional protein crosslinking reagent dimethyl 3,3'-dithiobispropionimidate-2HCl (DTBP) was used in an attempt to study alterations in the spatial arrangement of proteins in liver microsomal and plasma membranes that might be induced by dietary CPFA. The use of this reagent failed to yield a clear picture of protein-protein interactions in the microsomal membrane due to the formation of high molecular weight aggregates that were not resolvable on polyacrylamide gels. On the other hand, the use of DTBP failed to crosslink the proteins of the plasma membrane. In the third study, two-dimensional polyacrylamide gel electrophoresis was used to assess the effects of dietary CPFA on protein composition of trout liver microsomal and plasma membranes. Proteins were separated in the first dimension on the basis of their isoelectric points and in the second dimension on the basis of their molecular weights. No major alterations in the composition of liver microsomal or plasma membranes were found to be induced by dietary CPFA. / Graduation date: 1983

Monounsaturated fatty acids (MUFA) have been viewed as either beneficial or neutral with respect to health; however, recent evidence suggests that MUFA may be associated with obesity and cardiovascular disease. Sex differences in MUFA composition have been reported in both rats and humans that may be mediated by sex hormones. Therefore, differences in fatty acid and enzyme expression were examined in male and female rats. HepG2 cells treated with 17β-estradiol, progesterone and testosterone (0, 10, 30 and 100 nM), and ovariectomized female rats with hormone implants (sham, no treatment, estradiol, progesterone, and estradiol plus progesterone) examined the role of sex hormones in MUFA metabolism. MUFA concentrations were determined by gas chromatography. The mRNA and protein expression of stearoyl-CoA desaturase and elongase 6, key enzymes involved in MUFA biosynthesis, were measured by real-time PCR and immunoblotting, respectively. Elongase 6 protein expression was higher in females as compared with males, increased with estradiol and progesterone treatment of HepG2 cells, and was higher in ovariectomized rats treated with estradiol. Elongase 6 expression was also decreased in HepG2 cells treated with testosterone. In contrast, the expression of stearoyl-CoA desaturase did not appear to be associated with sex or sex hormones in HepG2 cells, although ovariectomized rats treated with estradiol plus progesterone had increased stearoyl-CoA desaturase protein levels compared with sham controls. Sex differences and differences after hormonal treatments were observed in the fatty acid concentrations of MUFA and immediate MUFA substrates including 16:0, 16:1n-7, 18:0, 18:1n-7 and 18:1n-9. These differences in MUFA are consistent with the changes in elongase 6 expression. The effect of sex and hormone status on elongase 6 has not been previously examined, but these results suggest elongase 6 is an important factor in determining MUFA composition. These sex and hormonal differences in MUFA composition may contribute to sex differences in obesity and cardiovascular disease. Further work examining other factors involved in MUFA composition including oxidation, synthesis of complex lipids and the effect of diet is required.

Thesis--Faculté de médecine de Paris, 1871. / Title continuation and author statement transposed from head of title. "Faculté de médecine de Paris, no. 33." Dédicace (p. 3) followed by a manuscript revision of the dedicatory text in ink, apparently in the author's hand. Number 4 in a bound vol. of 6 dissertations. DNLM DNLM Also available online.

Thesis (Ph. D.)--University of Texas at Austin, 2003. / Supervisor: Hung-wen Liu. Vita. Includes bibliographical references. Also available from UMI.

Thesis (M. Phil.)--University of Hong Kong, 1989.

Thesis (M. Phil.)--University of Hong Kong, 1989.

No description available.

published_or_final_version / Chemistry / Master / Master of Philosophy

published_or_final_version / Chemistry / Master / Master of Philosophy