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Head and neck cancer is diagnosed in more than 50,000 Americans each year, resulting in roughly 11,000 deaths. For this disease, a typical therapeutic regimen involves cisplatin, a radiosensitizer, given alongside targeted irradiation. While technological advances such as IMRT have been useful in sparing normal tissues from radiotherapy, the salivary glands occupy much of the head and neck and surround several lymph nodes, and thus, non-diseased salivary glands are often damaged. This causes reduced salivary output, damaged oral mucosa, dysphagia, malnutrition and tooth decay. Often, these side-effects are so severe that patients discontinue treatment, however, in many cases, salivary gland damage is permanent, and treatment options are palliative. Specifically, muscarinic-cholinergic agonists are used to enhance secretion from remaining salivary cells, although due to non-specific action, these drugs have a number of ill-effects. It is clear that therapies are needed to prevent radiation-induced salivary gland damage, as well as to restore glandular function in patients who are already suffering.Previous work from our group has shown that salivary gland dysfunction results from loss of acinar cells to radiation-induced apoptosis. Importantly, a single intravenous dose of IGF1 can prevent apoptosis and preserve salivary output when given immediately prior to irradiation. Because of its broad effects, however, IGF1 may never be a viable clinical option. Instead, our goal is to identify signaling events that mediate the radioprotective effects of IGF1 downstream of Akt. Because radiation-induced apoptosis in salivary glands is p53-dependent, we assessed the contributions of the p53 homologs p63 and p73 to the DNA damage response. Here, we show that IGF1 enhances cell cycle arrest following irradiation by reducing inhibitory binding of deltaNp63 to the p21 promoter. We hypothesize that IGF1-induced cell cycle arrest may allow time for DNA repair, thus preventing apoptosis and maintaining salivary function. In addition, we indicate chronic signaling events downstream of p63 that may contribute to permanent loss of salivary function by blocking differentiation of salivary progenitor cells. Together, these results indicate that p63 may be a valid therapeutic target for both prevention of damage and restoration of function in irradiated salivary glands.

I tested a prevalent assumption in glucocorticoid research that states that each species has a dominant glucocorticoid, and cortisol and corticosterone are interchangeable steroids. A comprehensive analysis of historical and current data failed to support this assumption and revealed evidence of drift away from exploration of cortisol and corticosterone as dual, important adrenal products to the exclusive quantification of one, dominant glucocorticoid. Originating approximately 30 years ago, the dominant glucocorticoid/ interchangeability assumption is now portrayed in textbook images used to represent adrenal steroid biosynthesis and is widespread throughout empirical research. Less than 1% of over 50,000 published papers relating to the glucocorticoids have considered the potential for independence in glucocorticoid signaling by quantifying both cortisol and corticosterone within a sample. A dispersed literature shows independent regulation of cortisol and corticosterone, extensive inter-species variation in glucocorticoid concentrations and cortisol: corticosterone ratios and adrenal synthesis of the non-dominant glucocorticoid during early development. We hypothesize that there is a functional duality in glucocorticoid signaling and use mass spectrometry to explore the glucocorticoid profile of the full-term human (n = 125) and guinea pig (n = 28) fetus (both cortisol-dominant species). The sample preparation method yielded poor steroid recoveries (~ 4-28%), which made quantification by mass spectrometry challenging, but in both species corticosterone concentrations were significantly higher in fetal blood compared to umbilical venous or umbilical mixed blood (p < 0.0001), suggesting fetal corticosterone enrichment. Within an individual, cortisol was not an accurate predictor of corticosterone for either species (human, r = 0.001, p > 0.05; guinea pig, r = 0.14, p > 0.05) and our data suggests independent glucocorticoid responses; in humans, cortisol was significantly higher in vaginal deliveries relative to elective Caesarian sections (p < 0.0001) but corticosterone was unaffected. Guinea pig fetal corticosterone was not affected by daily maternal stress during gestation but cortisol was significantly lower in stressed fetuses (p < 0.05). While these preliminary data require further investigation, we conclude that fetuses from the human and guinea pig actively secrete the non-dominant glucocorticoid in late gestation and suggest that there is a functional duality in glucocorticoid signaling. / Thesis (Master, Biology) -- Queen's University, 2010-01-25 10:28:26.307

Adrenal glands from five species of South African antelope; cape eland (Taurotragus o.oryx), gemsbok (Oryx g.gazella), southern greater kudu (Tragelaphus s.strepsiceros), red hartebeest (Alcelaphus buselaphus caama), springbok (Antidorcas marsupialis hofmeyri), were collected from 43 trophy-hunted males for histology and corticosteroid analysis. The gross anatomy of the adrenal glands are species-specific, with the left gland being most variable. There were differences found in the number of cortex capsular layers and zona glomerulosa between species. Extensive capsular trabeculae penetrates deep into the cortex in only the largest antelope, i.e. eland and gemsbok, and are representative of these species. In all species the zona glomerulosa form variations in types of cellular cord structures, with the greater kudu having the most unique architecture of horizontally stratified, highly columnar cells that form winding cords which arches at the capsular end, and resemble those observed in equine species. Medullary capsules were observed in the eland, and incomplete capsules in the gemsbok and greater kudu. The medulla is characterized by an outer, adrenaline secreting zone that encapsulates a inner noradrenaline secreting zone in all species. The corticosteroid patterns are typical of bovids, with cortisol and corticosterone present, however significantly larger amounts of 18-hydroxy-corticosterone were found in all species of antelope. The total identified corticosteroid contents had interspecies differences, which are possibly based on species body size.

Introduction: Salivary gland obstructive conditions are common and may necessitate imaging of the glands for diagnosis and management purposes. Many imaging options are available but all have limitations. Sialography is considered the gold standard for examining obstructive conditions of the parotid and submandibular glands but it is largely influenced by the imaging technique to which it is coupled. Cone beam computed tomography (cbCT) is a relatively new and very promising imaging modality that has overcome many of the inherent limitations of other imaging modalities used in the past for sialography. Materials and methods: A RANDO®Man imaging phantom was used to determine the effective radiation doses from the series of plain film images that represent the current standard of practice for sialography. Similar experiments were then undertaken to determine the effective radiation doses from cbCT when varying the field-of-view (FOV) size and center, x-ray tube peak kilovoltage (kVp) and milliamperage (mA). Next, cbCT image quality, measured using the signal-difference-to-noise-ratio (SDNR) was used to determine those technical factors that optimized image quality. Finally, using the optimized image acquisition parameters, a prospective clinical study was conducted to test the diagnostic efficacy of cbCT sialography compared to plain film sialography. Results: Effective radiation doses were comparable between the plain film image series and cbCT examinations of the parotid and submandibular glands when a 6” FOV was chosen, and when the x-ray tube was operating at 80 kVp and 10 mA. We also found that these exposure settings optimized the image SDNR. Finally, we demonstrated that the diagnostic capabilities of cbCT sialography were superior to plain film sialography with regards to detecting sialoliths and strictures, and when differentiating normal salivary glands from those with changes secondary to inflammation. Conclusion: We have successfully developed a three dimensional (3D) sialography technique for imaging the parotid and submandibular salivary glands using cbCT that balances radiation effective dose with image quality. We also demonstrated the superior diagnostic capabilities of the new technique in a clinical setting.

Introduction: Salivary gland obstructive conditions are common and may necessitate imaging of the glands for diagnosis and management purposes. Many imaging options are available but all have limitations. Sialography is considered the gold standard for examining obstructive conditions of the parotid and submandibular glands but it is largely influenced by the imaging technique to which it is coupled. Cone beam computed tomography (cbCT) is a relatively new and very promising imaging modality that has overcome many of the inherent limitations of other imaging modalities used in the past for sialography. Materials and methods: A RANDO®Man imaging phantom was used to determine the effective radiation doses from the series of plain film images that represent the current standard of practice for sialography. Similar experiments were then undertaken to determine the effective radiation doses from cbCT when varying the field-of-view (FOV) size and center, x-ray tube peak kilovoltage (kVp) and milliamperage (mA). Next, cbCT image quality, measured using the signal-difference-to-noise-ratio (SDNR) was used to determine those technical factors that optimized image quality. Finally, using the optimized image acquisition parameters, a prospective clinical study was conducted to test the diagnostic efficacy of cbCT sialography compared to plain film sialography. Results: Effective radiation doses were comparable between the plain film image series and cbCT examinations of the parotid and submandibular glands when a 6” FOV was chosen, and when the x-ray tube was operating at 80 kVp and 10 mA. We also found that these exposure settings optimized the image SDNR. Finally, we demonstrated that the diagnostic capabilities of cbCT sialography were superior to plain film sialography with regards to detecting sialoliths and strictures, and when differentiating normal salivary glands from those with changes secondary to inflammation. Conclusion: We have successfully developed a three dimensional (3D) sialography technique for imaging the parotid and submandibular salivary glands using cbCT that balances radiation effective dose with image quality. We also demonstrated the superior diagnostic capabilities of the new technique in a clinical setting.

Radiotherapy of malignancies in the head and neck often involves the major and minor salivary glands in the radiation field. Adverse effects, such as dry mouth symptoms, are common after such therapy. The aim of this thesis was to study longitudinal effects of fractionated irradiation to the head and neck on salivary gland function in man and in the rat and to test radioprotection from antioxidant vitamins (retinol, a-tocopherol and ^-carotene). A sharp decrease in parotid saliva flow rate was seen after one week of irradiation in cancer patients, but in some patients recovery was seen two months after completed treatment. Loss and recovery of salivary gland function were dependent on the total dose given. Irradiation with doses of &gt;65 Gy to the parotid glands led to permanent loss of function in the majority of parotid glands, while recovery could be seen after irradiation with doses of &lt;52 Gy. Concentrations of some proteins and electrolytes in saliva were increased during irradiation but no changes remained 18 months after radiotherapy. However, large inter-individual differences were seen. The irradiation effects observed in rats did not greatly differ from those seen in humans, but no recovery of salivary gland function was seen. On the one hand the impairments of saliva flow and composition w ere dose and time dependent, but on the other hand the response pattem differed between salivary components. Morphological alterations were not seen in the rat salivary' glands after tw'O or five weeks but 26 weeks after irradiation. No single model seems to be optimal for studying all parameters. Therefore, to study effects on salivary glands after irradiation the rat model must be adjusted to meet the questions addressed. Supplementation with vitamin A provided no radioprotection, whereas it w'as found that supplementation with a-tocopherol (3.4 mg/day) and ß-carotene (6 mg/day) during irradiation reduced the degree of inflammation and partly preserved salivary gland function. It did not, however, lead to morphometrically detectable differences in proportions of acinar or ductal cells or stroma.Keywords: Irradiation, salivary glands, saliva composition, antioxidants / <p>S. 1-82: sammanfattning, s. 85-152: 6 uppsatser</p> / digitalisering@umu

This study was designed to determine the distribution of fatty acids and cholesterol in total tumor and mammary tissues. Fatty acid profiles of phospholipid fractions from tumors and mammary glands were also determined. Fatty acids and cholesterols were analyzed by gas liquid chromatography. Methodology was developed for phospholipid separation by high performance liquid chromatography.Tumors derived from mammary glands in Strain A/ST mice were found to contain two to three times the amount of cholesterol compared to normal mammary glands. Mammary glands from safflower fed mice contained significantly higher percentages of linoleic acid. Linoleic acid content in stearicacid (SA-1) fed mice was sharply reduced. linoleic acid in mammary glands of animals fed a high fat Stearic acid (SA-4) , corn oil and stock diet fed animals displayed similar fatty acid profiles. Fatty acid analysis of tumors excised from mice fed the experimental diets showed similar patterns in comparison to normal mammary glands. The similar distributions were in the 18 carbon fatty acids. Distributions of phospholipid fatty acids in tumors and mammary glands were similar. Mammary gland phospholipids displayed increased percentages of short chain (14 carbons and under) fatty acids. Results of these studies demonstrate an increased availability of diet rich in polyunsaturated fatty acids.

The extracellular matrix (ECM) plays an important role in mammary gland development and function. Osteopontin (OPN), a secreted glycophosphoprotein, with several functional and structural properties of ECM proteins, is expressed at elevated levels during normal and pathologic development of the mammary gland and is present in milk. However, whether it plays any developmental role in the mammary gland is unknown. To investigate this possibility, transgenic AS-OPN mice were generated using a transgene expressing OPN antisense RNA under the control of the MMTV-LTR promoter/enhancer. The mammary glands of AS-OPN mice express low levels of OPN, compared to control littermates, show excessive branching of the ductal epithelium at the virgin stage, impaired proliferation of the mammary epithelium, and abnormal alveolar structure formation during pregnancy, and mild to severe lactation deficiency. To further examine the role of OPN at the cellular level, an established murine mammary epithelial cell line (NMuMG), which is capable of differentiation in culture, was transfected with the same DNA construct used to generate AS-OPN mice. Several antisense OPN cDNA transfected clones, which secrete decreased amounts of OPN compared to mock-transfected cells were obtained. These cells were found to have lost their ability to form branched duct-like structures, as judged by branching morphogenesis assays, by growth in collagen gels and stimulation with hepatocyte growth factor. They also failed to spread on type I collagen, although their binding to type IV collagen was unaffected. The antisense transfectants also assumed a mesenchymal phenotype, characterized by fibroblast-like morphology, an apparent loss of cell-cell contacts and spontaneous cell scattering. Transmigration assays and wounding experiments indicated that these cells also have a higher migratory activity than control cells. Northern blot and immunofluorescence analyses showed that migrating cells downregulate OP

Addendum pasted onto front end-paper. / Bibliography: leaves 214-226. / v, 227, [7] leaves, [71] leaves of plates : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.A)--University of Adelaide, Dept. of Anatomical Sciences, 1998?