+publisher:"University of Arizona" +contributor:("Limesand, Kirsten H.")

University of Arizona

1. Morgan-Bathke, Maria Elizabeth. The Role of Autophagy in Salivary Gland Dysfunction Following Targeted Head and Neck Radiation .

Degree: 2013, University of Arizona

URL: http://hdl.handle.net/10150/301532

► Head and neck cancer is one of the most common cancers worldwide. The current standard of care for head and neck cancer includes surgical resection… (more)

▼ Head and neck cancer is one of the most common cancers worldwide. The current standard of care for head and neck cancer includes surgical resection of the tumor followed by chemoradiation. This targeted head and neck radiation causes dysfunction of the salivary glands, which leads to xerostomia, mucositis, dysphagia, dental caries, and malnutrition. These side effects greatly decrease patient quality of life and increase their financial responsibility. Current therapies available to ameliorate these negative side effects are expensive, only provide short-term relief, and many of them have negative side effects of their own. Therefore, another therapy is needed to prevent salivary gland dysfunction or restore its function following targeted head and neck radiation. Autophagy is a homeostatic cellular mechanism that could be targeted as a therapeutic mechanism in the salivary glands following targeted head and neck radiation. Autophagy is a catabolic process necessary to maintain cellular homeostasis. It has been shown to play a beneficial role in a variety of disease states including diabetes mellitus, obesity, and cancer. The role of autophagy in the response of cancerous tissue to radiation has been vastly studied. However, the role autophagy plays in normal tissue response to radiation remains poorly understood and much more research in this area is needed.Atg5^(f/f);Aqp5-Cre mice have a conditional knockout of Atg5, a gene necessary for autophagy, in the salivary glands. These mice have unchanged baseline levels of apoptosis, proliferation, and stimulated salivary flow rates when compared to wild-type mice. Therefore, they are a useful model to investigate the role of autophagy in the response of the salivary glands to targeted head and neck radiation. These Atg5^(f/f);Aqp5-Cre autophagy-deficient mice display increased radiosensitivity following targeted head and neck radiation. Furthermore, post-therapy use of CCI-779, a rapalogue and inducer of autophagy, allowed for restoration of salivary gland function following targeted head and neck radiation. Taken together, these results implicate autophagy as playing a beneficial role in normal salivary function following radiation. Therefore, autophagy could be utilized by normal salivary gland tissue following targeted head and neck radiation to maintain salivary gland function. Advisors/Committee Members: Limesand, Kirsten H (advisor), Burd, Randy (committeemember), Thomson, Cynthia (committeemember), Limesand, Kirsten H. (committeemember).

Subjects/Keywords: head and neck cancer; radiation; salivary gland; Nutritional Sciences; autophagy

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APA (6^th Edition):

Morgan-Bathke, M. E. (2013). The Role of Autophagy in Salivary Gland Dysfunction Following Targeted Head and Neck Radiation . (Doctoral Dissertation). University of Arizona. Retrieved from http://hdl.handle.net/10150/301532

Chicago Manual of Style (16^th Edition):

Morgan-Bathke, Maria Elizabeth. “The Role of Autophagy in Salivary Gland Dysfunction Following Targeted Head and Neck Radiation .” 2013. Doctoral Dissertation, University of Arizona. Accessed March 05, 2021. http://hdl.handle.net/10150/301532.

MLA Handbook (7^th Edition):

Morgan-Bathke, Maria Elizabeth. “The Role of Autophagy in Salivary Gland Dysfunction Following Targeted Head and Neck Radiation .” 2013. Web. 05 Mar 2021.

Vancouver:

Morgan-Bathke ME. The Role of Autophagy in Salivary Gland Dysfunction Following Targeted Head and Neck Radiation . [Internet] [Doctoral dissertation]. University of Arizona; 2013. [cited 2021 Mar 05]. Available from: http://hdl.handle.net/10150/301532.

Council of Science Editors:

Morgan-Bathke ME. The Role of Autophagy in Salivary Gland Dysfunction Following Targeted Head and Neck Radiation . [Doctoral Dissertation]. University of Arizona; 2013. Available from: http://hdl.handle.net/10150/301532

University of Arizona

2. Martinez Chibly, Agustin Alejandro. Functional Restoration of Irradiated Salivary Glands Through Modulation of aPKCζ and Nuclear Yap in Salivary Progenitors .

Degree: 2016, University of Arizona

URL: http://hdl.handle.net/10150/621771

► Radiotherapy is the primary treatment for patients with head and neck cancer, which account for roughly 60,000 annual diagnoses in the U.S. and approximately 500,000… (more)

▼ Radiotherapy is the primary treatment for patients with head and neck cancer, which account for roughly 60,000 annual diagnoses in the U.S. and approximately 500,000 worldwide. About 90% of these individuals receive radiation therapy, and salivary hypofunction and xerostomia occur in 60-85% of these patients due to irreversible damage to the salivary glands. Current preventative and palliative care fail to improve quality of life, accentuating the need for regenerative therapies. Stem/progenitor-cell based therapies have been proposed to regenerate the irradiated glands; however, the identity of stem and progenitor cells in the adult salivary glands has remained somewhat elusive. Moreover, it is unclear how salivary progenitors respond to radiation and whether they can be stimulated to effectively reinstate salivary function. The second chapter of the present study describes the development of a label-retaining assay in salivary glands using EdU. The label-retaining cells (LRCs) identified in murine salivary glands have proliferative potential in vitro and expressed markers of putative salivary progenitors, such as Keratin 5, Keratin 14, and c-Kit. Interestingly, LRCs were still present 30 days following radiation, when chronic loss of saliva is evident. The significance of these findings lies in the potential of this model to study the mechanisms that prevent salivary progenitors from maintaining salivary gland homeostasis upon exposure to radiation, which will in turn facilitate the development of regenerative therapies for salivary gland dysfunction. In the following chapter, we show that a unique population of murine salivary gland LRCs undergo compensatory proliferation in response to radiation. The initiation of compensatory proliferation is tightly associated with inactivation of the kinase aPKCζ and increased nuclear localization of YAP. This part of the study provides novel insights into the regulation of function of salivary gland progenitors, which can be utilized for the development of therapeutic agents to treat salivary hypofunction. Finally, the last chapter describes how the mechanisms found to initiate compensatory proliferation in acinar LRCs as a response to radiation are involved in the regeneration of salivary glands with IGF-1. Administration of IGF-1 post-radiation restores salivary function in mice, but the mechanisms of regeneration are still unknown. Here, we show that IGF-1 requires aPKCζ to restore saliva production. Further, IGF-1 inhibits nuclear translocation of Yap in an aPKCζ-dependent fashion. We propose that a tightly regulated balance in the levels of aPKCζ and Yap in acinar LRCs has to be maintained in order to restore function following radiation. In conclusion, the findings from this study provide new knowledge in regards to the regulation of function of salivary progenitors during a state of injury (by radiation) and during regeneration (with IGF), and offer potential targets of study for the development of new therapeutics for salivary gland dysfunction. Future studies will… Advisors/Committee Members: Limesand, Kirsten H (advisor), Limesand, Kirsten H. (committeemember), Wilson, Jean (committeemember), Briehl, Margaret (committeemember), Burd, Randy (committeemember).

Subjects/Keywords: IGF-1; Radiation; Salivary Glands; Yap; Cancer Biology; aPKCζ

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APA (6^th Edition):

Martinez Chibly, A. A. (2016). Functional Restoration of Irradiated Salivary Glands Through Modulation of aPKCζ and Nuclear Yap in Salivary Progenitors . (Doctoral Dissertation). University of Arizona. Retrieved from http://hdl.handle.net/10150/621771

Chicago Manual of Style (16^th Edition):

Martinez Chibly, Agustin Alejandro. “Functional Restoration of Irradiated Salivary Glands Through Modulation of aPKCζ and Nuclear Yap in Salivary Progenitors .” 2016. Doctoral Dissertation, University of Arizona. Accessed March 05, 2021. http://hdl.handle.net/10150/621771.

MLA Handbook (7^th Edition):

Martinez Chibly, Agustin Alejandro. “Functional Restoration of Irradiated Salivary Glands Through Modulation of aPKCζ and Nuclear Yap in Salivary Progenitors .” 2016. Web. 05 Mar 2021.

Vancouver:

Martinez Chibly AA. Functional Restoration of Irradiated Salivary Glands Through Modulation of aPKCζ and Nuclear Yap in Salivary Progenitors . [Internet] [Doctoral dissertation]. University of Arizona; 2016. [cited 2021 Mar 05]. Available from: http://hdl.handle.net/10150/621771.

Council of Science Editors:

Martinez Chibly AA. Functional Restoration of Irradiated Salivary Glands Through Modulation of aPKCζ and Nuclear Yap in Salivary Progenitors . [Doctoral Dissertation]. University of Arizona; 2016. Available from: http://hdl.handle.net/10150/621771

University of Arizona

3. Meyer, Rachel Katherine. AMP-Activated Protein Kinase Activation Impacts Cell Proliferation and Salivary Flow Rates Following Radiation Therapy .

Degree: 2019, University of Arizona

URL: http://hdl.handle.net/10150/634392

► Head and neck cancers remain the sixth most common cancer worldwide and represent over 600,000 new cases diagnosed annually. Typical treatment of early-stage head and… (more)

Subjects/Keywords: AMPK; Cell Biology; Metformin; Radiation; Salivary glands; Xerostomia

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APA (6^th Edition):

Meyer, R. K. (2019). AMP-Activated Protein Kinase Activation Impacts Cell Proliferation and Salivary Flow Rates Following Radiation Therapy . (Masters Thesis). University of Arizona. Retrieved from http://hdl.handle.net/10150/634392

Chicago Manual of Style (16^th Edition):

Meyer, Rachel Katherine. “AMP-Activated Protein Kinase Activation Impacts Cell Proliferation and Salivary Flow Rates Following Radiation Therapy .” 2019. Masters Thesis, University of Arizona. Accessed March 05, 2021. http://hdl.handle.net/10150/634392.

MLA Handbook (7^th Edition):

Meyer, Rachel Katherine. “AMP-Activated Protein Kinase Activation Impacts Cell Proliferation and Salivary Flow Rates Following Radiation Therapy .” 2019. Web. 05 Mar 2021.

Vancouver:

Meyer RK. AMP-Activated Protein Kinase Activation Impacts Cell Proliferation and Salivary Flow Rates Following Radiation Therapy . [Internet] [Masters thesis]. University of Arizona; 2019. [cited 2021 Mar 05]. Available from: http://hdl.handle.net/10150/634392.

Council of Science Editors:

Meyer RK. AMP-Activated Protein Kinase Activation Impacts Cell Proliferation and Salivary Flow Rates Following Radiation Therapy . [Masters Thesis]. University of Arizona; 2019. Available from: http://hdl.handle.net/10150/634392

4. Contreras, Nico Anthony. Environmental Impact on Lifelong Immunity: The Role of Infection and Nutrition in Host Homeostasis .

Degree: 2019, University of Arizona

URL: http://hdl.handle.net/10150/634344

► The impact of environmental pressures on the immune system is significant and complex. External influences contribute to immune development, cause or impact diseases, and fundamentally… (more)

Subjects/Keywords: Adipose; Age; Calorie Restriction; Cytomegalovirus; Lymphocyte; T-cell

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APA (6^th Edition):

Contreras, N. A. (2019). Environmental Impact on Lifelong Immunity: The Role of Infection and Nutrition in Host Homeostasis . (Doctoral Dissertation). University of Arizona. Retrieved from http://hdl.handle.net/10150/634344

Chicago Manual of Style (16^th Edition):

Contreras, Nico Anthony. “Environmental Impact on Lifelong Immunity: The Role of Infection and Nutrition in Host Homeostasis .” 2019. Doctoral Dissertation, University of Arizona. Accessed March 05, 2021. http://hdl.handle.net/10150/634344.

MLA Handbook (7^th Edition):

Contreras, Nico Anthony. “Environmental Impact on Lifelong Immunity: The Role of Infection and Nutrition in Host Homeostasis .” 2019. Web. 05 Mar 2021.

Vancouver:

Contreras NA. Environmental Impact on Lifelong Immunity: The Role of Infection and Nutrition in Host Homeostasis . [Internet] [Doctoral dissertation]. University of Arizona; 2019. [cited 2021 Mar 05]. Available from: http://hdl.handle.net/10150/634344.

Council of Science Editors:

Contreras NA. Environmental Impact on Lifelong Immunity: The Role of Infection and Nutrition in Host Homeostasis . [Doctoral Dissertation]. University of Arizona; 2019. Available from: http://hdl.handle.net/10150/634344

University of Arizona

5. Kunihiro, Andrew. Bone-Specific Metabolism and Mechanism of Action of Curcuminoids in Blocking Osteolysis in Breast Cancer and Other Resorptive Bone Diseases .

Degree: 2019, University of Arizona

URL: http://hdl.handle.net/10150/636687

► Osteoclast-mediated bone resorptive disorders, including post-menopausal osteoporosis, age-related bone loss, rheumatoid arthritis, and osteolytic bone metastases, affect over 55 million Americans each year. Breast cancer… (more)

▼ Osteoclast-mediated bone resorptive disorders, including post-menopausal osteoporosis, age-related bone loss, rheumatoid arthritis, and osteolytic bone metastases, affect over 55 million Americans each year. Breast cancer bone metastases, the model of bone resorptive disorders to be used here, causes osteolysis through a “vicious cycle”, whereby osteoclasts release growth factors (e.g., TGFβ) stored in the bone, which can cause bone-metastatic tumor cells to secrete pro-osteolytic factors (e.g., PTHrP), resulting in more osteoclast-mediated bone resorption. Curcuminoids, dietary polyphenols derived from the turmeric rhizome, inhibit progression of osteolytic bone metastases and other resorptive diseases by targeting osteoclasts and – in the case of bone metastases, also blocking tumoral TGFβ signaling – despite circulating as a glucuronide conjugate that is posited to lack bioactivity. These studies demonstrated that curcumin-glucuronide did not inhibit tumoral TGFβ signaling, with confirmation in multiple breast cancer cell lines that form TGFβ-dependent osteolytic lesions, nor did it inhibit osteoclastogenesis, with both TGFβ signaling and osteoclastogenesis being central to this osteolytic feed-forward loop. However, mouse bone marrow β-glucuronidase (GUSB) deconjugated curcumin-glucuronide to the active aglycone, which was maintained across sexual and skeletal development and with bone resorptive disorders, with evidence that human bone marrow also has deconjugation activity. Other bone-protective dietary polyphenols (e.g., quercetin and resveratrol) were also deconjugated by bone marrow, a GUSB-mediated effect that was required for bone-protective bioactivity, suggesting that GUSB-mediated deconjugation of abundantly glucuronidated dietary polyphenols may be a universal requirement to derive benefits. Finally, curcuminoids inhibited tumoral TGFβ signaling by reducing protein levels of TGFβR2 (receptor that binds TGFβ) and Smad2 (phosphorylated by TGFβR1 following activation of TGFβR2 to stimulate genes promoting bone metastasis progression) primarily through effects on gene expression that depended, in part, on oxidative metabolism. In toto, these novel findings answer a long-standing question about curcumin’s apparent lack of bioavailability, with implications for the bioactivity of other dietary polyphenols, and provide a framework for future studies to explore how interindividual GUSB expression in the population may impact both curcumin’s bone-protective bioactivity and its side effects as well as to further provide insight into cellular targets underlying curcumin’s inhibition of signaling pathways important in bone resorption. Advisors/Committee Members: Funk, Janet L (advisor), Doetschman, Thomas C. (committeemember), Limesand, Kirsten H. (committeemember), Romagnolo, Donato F. (committeemember).

Subjects/Keywords: cancer; curcumin; metastasis

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Kunihiro, A. (2019). Bone-Specific Metabolism and Mechanism of Action of Curcuminoids in Blocking Osteolysis in Breast Cancer and Other Resorptive Bone Diseases . (Doctoral Dissertation). University of Arizona. Retrieved from http://hdl.handle.net/10150/636687

Chicago Manual of Style (16^th Edition):

Kunihiro, Andrew. “Bone-Specific Metabolism and Mechanism of Action of Curcuminoids in Blocking Osteolysis in Breast Cancer and Other Resorptive Bone Diseases .” 2019. Doctoral Dissertation, University of Arizona. Accessed March 05, 2021. http://hdl.handle.net/10150/636687.

MLA Handbook (7^th Edition):

Kunihiro, Andrew. “Bone-Specific Metabolism and Mechanism of Action of Curcuminoids in Blocking Osteolysis in Breast Cancer and Other Resorptive Bone Diseases .” 2019. Web. 05 Mar 2021.

Vancouver:

Kunihiro A. Bone-Specific Metabolism and Mechanism of Action of Curcuminoids in Blocking Osteolysis in Breast Cancer and Other Resorptive Bone Diseases . [Internet] [Doctoral dissertation]. University of Arizona; 2019. [cited 2021 Mar 05]. Available from: http://hdl.handle.net/10150/636687.

Council of Science Editors:

Kunihiro A. Bone-Specific Metabolism and Mechanism of Action of Curcuminoids in Blocking Osteolysis in Breast Cancer and Other Resorptive Bone Diseases . [Doctoral Dissertation]. University of Arizona; 2019. Available from: http://hdl.handle.net/10150/636687

University of Arizona

6. Villa Guillen, Diana Evelyn. Breast Density and Metabolic Risk Factors: A Cross-Sectional Analysis of a Phase II Study in Premenopausal Women with Elements of Metabolic Syndrome .

Degree: 2018, University of Arizona

URL: http://hdl.handle.net/10150/628460

► Background Breast density is an established breast cancer risk factor. Metabolic disturbances and high adiposity also increase breast cancer burden, but their relationships with breast… (more)

▼ Background Breast density is an established breast cancer risk factor. Metabolic disturbances and high adiposity also increase breast cancer burden, but their relationships with breast density are not defined. This dissertation research aims to provide more evidence of the associations of metabolic risk factors with breast density measures in a cohort of premenopausal women with elements of metabolic syndrome. Experimental Design We performed this dissertation research within the context of a Phase II clinical trial conducted at the University of Arizona Cancer Center in overweight or obese premenopausal women with metabolic dysregulations. The primary aim of the trial was to evaluate if metformin intervention for 12 months can exert changes in breast density. A cross-sectional analysis was performed using the baseline data of the study cohort to evaluate the associations of breast density measurements with metabolic disturbances. The breast density measures, acquired by fat-water MRI, included absolute dense volume, percent density, non-dense volume, and total breast volume. The measures of metabolic disturbances included anthropometric measures, elements of metabolic syndrome, insulin/insulin-like growth factor (IGF) axis, and adipokines. Results Our findings indicate that each breast density measurement is non-normally distributed and comprised of distinct subpopulations with normal distributions. We correlated the breast density measurements with anthropometric measures. Those relationships were unaffected by ethnicity but were affected by age and reproductive factors. Total breast volume and non-dense volume were positively related to waist circumference, a measure of central adiposity, after adjustment for potential confounders (i.e., adiposity, ethnicity, age, reproductive factors). These two density measures were also positively correlated with serum leptin levels following adjustment of potential confounders, including waist circumference, but not with other measures of metabolic disturbance. Individuals with elevated fasting glucose had lower absolute dense volume. The insulin and HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) were inversely related to the absolute dense volume after adjustment for potential confounders. In addition, we observed a positive correlation between the absolute dense volume and serum leptin levels. Individuals with elevated fasting glucose had a lower percent density. Individuals with elevated fasting glucose had lower percent density but showed no correlation with insulin and HOMA-IR in analysis adjusted for potential confounders. Furthermore, percent density was positively related to a measure of bioavailable IGF-1 (molar ratio of IGF-1/IGF binding protein 3). Conclusion The heterogeneity of breast density measures indicates that there is a wide range of values within our cohort. The observed associations between breast density measures with selected metabolic disturbances suggest the importance of considering these metabolic disturbances when evaluating breast… Advisors/Committee Members: Chow, Hsiao-Hui (Sherry) (advisor), Romagnolo, Donato F (advisor), Funk, Janet L. (committeemember), Laukaitis, Christina M. (committeemember), Martinez, Jessica A. (committeemember), Limesand, Kirsten H. (committeemember).

Subjects/Keywords: Breast cancer; Chemoprevention; Clinical trials; Obesity

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APA (6^th Edition):

Villa Guillen, D. E. (2018). Breast Density and Metabolic Risk Factors: A Cross-Sectional Analysis of a Phase II Study in Premenopausal Women with Elements of Metabolic Syndrome . (Doctoral Dissertation). University of Arizona. Retrieved from http://hdl.handle.net/10150/628460

Chicago Manual of Style (16^th Edition):

Villa Guillen, Diana Evelyn. “Breast Density and Metabolic Risk Factors: A Cross-Sectional Analysis of a Phase II Study in Premenopausal Women with Elements of Metabolic Syndrome .” 2018. Doctoral Dissertation, University of Arizona. Accessed March 05, 2021. http://hdl.handle.net/10150/628460.

MLA Handbook (7^th Edition):

Villa Guillen, Diana Evelyn. “Breast Density and Metabolic Risk Factors: A Cross-Sectional Analysis of a Phase II Study in Premenopausal Women with Elements of Metabolic Syndrome .” 2018. Web. 05 Mar 2021.

Vancouver:

Villa Guillen DE. Breast Density and Metabolic Risk Factors: A Cross-Sectional Analysis of a Phase II Study in Premenopausal Women with Elements of Metabolic Syndrome . [Internet] [Doctoral dissertation]. University of Arizona; 2018. [cited 2021 Mar 05]. Available from: http://hdl.handle.net/10150/628460.

Council of Science Editors:

Villa Guillen DE. Breast Density and Metabolic Risk Factors: A Cross-Sectional Analysis of a Phase II Study in Premenopausal Women with Elements of Metabolic Syndrome . [Doctoral Dissertation]. University of Arizona; 2018. Available from: http://hdl.handle.net/10150/628460

University of Arizona

7. Mitchell, Geoffrey C. The p53 homolog p63 modulates acute and chronic damage in irradiated salivary glands .

Degree: 2010, University of Arizona

URL: http://hdl.handle.net/10150/194089

► 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… (more)

▼ 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. Advisors/Committee Members: Limesand, Kirsten H (advisor), Burd, Randy (committeemember), Gerner, Eugene (committeemember), Briehl, Margaret (committeemember), Martinez, Jesse (committeemember).

Subjects/Keywords: Notch; p21; p53; p63; salivary glands; xerostomia

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APA (6^th Edition):

Mitchell, G. C. (2010). The p53 homolog p63 modulates acute and chronic damage in irradiated salivary glands . (Doctoral Dissertation). University of Arizona. Retrieved from http://hdl.handle.net/10150/194089

Chicago Manual of Style (16^th Edition):

Mitchell, Geoffrey C. “The p53 homolog p63 modulates acute and chronic damage in irradiated salivary glands .” 2010. Doctoral Dissertation, University of Arizona. Accessed March 05, 2021. http://hdl.handle.net/10150/194089.

MLA Handbook (7^th Edition):

Mitchell, Geoffrey C. “The p53 homolog p63 modulates acute and chronic damage in irradiated salivary glands .” 2010. Web. 05 Mar 2021.

Vancouver:

Mitchell GC. The p53 homolog p63 modulates acute and chronic damage in irradiated salivary glands . [Internet] [Doctoral dissertation]. University of Arizona; 2010. [cited 2021 Mar 05]. Available from: http://hdl.handle.net/10150/194089.

Council of Science Editors:

Mitchell GC. The p53 homolog p63 modulates acute and chronic damage in irradiated salivary glands . [Doctoral Dissertation]. University of Arizona; 2010. Available from: http://hdl.handle.net/10150/194089

University of Arizona

8. Hernandez, Laura L. Characterization of the Bovine Mammary Gland Serotonergic System .

Degree: 2007, University of Arizona

URL: http://hdl.handle.net/10150/196049

► Previous research indicates the presence of a feedback inhibitor of lactation (FIL) in milk (Peaker and Wilde, 1996). Recently, tryptophan hydroxylase I (TPH1), the rate-limiting… (more)

▼ Previous research indicates the presence of a feedback inhibitor of lactation (FIL) in milk (Peaker and Wilde, 1996). Recently, tryptophan hydroxylase I (TPH1), the rate-limiting enzyme in serotonin (5-HT) biosynthesis, was identified in the mouse mammary gland and to be regulated by prolactin (PRL). Furthermore, 5-HT was present in rodent milk and addition of 5-HT to in vitro mammary cultures and in vivo administration of 5-HT to lactating mice reduced milk protein synthesis. Studies were conducted to determine the presence of the enzymatic machinery necessary to produce 5-HT in the bovine mammary gland, the presence of specific 5-HT receptors within the bovine mammary gland, the effects of 5-HT and non-selective and selective receptor antagonists on milk protein gene expression in cultures of primary bovine mammary epithelial cells (BMEC), and to determine the effects of intra-mammary infusions of 5-HT and a non-selective 5-HT receptor antagonist on milk production and composition in lactating dairy cows. Tryptophan hydroxylase I, aromatic amino acid decarboxylase (AADC) and the 5-HT reuptake transporter (SERT) were detected in lactating bovine mammary tissue by qRT-PCR and immunohistochemical staining. Additionally, mRNA for the 5-HT 1B, 2A, 2B, 4 and 7 receptors were detected in bovine mammary tissue as well as BMEC by qRT-PCR and in situ hybridization. Tryptophan hydroxylase I mRNA is in BMEC and up-regulated by PRL. Serotonin down-regulates milk protein gene expression but has not apparent effects on apoptosis and methysergide, ritanserin, SB-224289, and pimozide (receptor antagonists) increased milk protein gene expression in BMEC. Intra-mammary 5-HT infusions decreased overall milk yield in late-lactating dairy cows by 11.1%. Intra-mammary infusions of METH increased overall milk yield by 10.9%. In conclusion, the enzymatic machinery for 5-HT biosynthesis and uptake, as well as receptors involved 5-HT signaling are present in the bovine mammary gland. Furthermore, 5-HT appears to be a FIL in the bovine, but further research regarding its cellular mechanism of action and the location of its receptor populations should be conducted. Advisors/Committee Members: Collier, Robert J (advisor), Baumgard, Lance H (advisor), Horseman, Nelson D. (committeemember), Limesand, Kirsten H. (committeemember), Goll, Darrel E. (committeemember).

Subjects/Keywords: Nutritional Sciences

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APA (6^th Edition):

Hernandez, L. L. (2007). Characterization of the Bovine Mammary Gland Serotonergic System . (Doctoral Dissertation). University of Arizona. Retrieved from http://hdl.handle.net/10150/196049

Chicago Manual of Style (16^th Edition):

Hernandez, Laura L. “Characterization of the Bovine Mammary Gland Serotonergic System .” 2007. Doctoral Dissertation, University of Arizona. Accessed March 05, 2021. http://hdl.handle.net/10150/196049.

MLA Handbook (7^th Edition):

Hernandez, Laura L. “Characterization of the Bovine Mammary Gland Serotonergic System .” 2007. Web. 05 Mar 2021.

Vancouver:

Hernandez LL. Characterization of the Bovine Mammary Gland Serotonergic System . [Internet] [Doctoral dissertation]. University of Arizona; 2007. [cited 2021 Mar 05]. Available from: http://hdl.handle.net/10150/196049.

Council of Science Editors:

Hernandez LL. Characterization of the Bovine Mammary Gland Serotonergic System . [Doctoral Dissertation]. University of Arizona; 2007. Available from: http://hdl.handle.net/10150/196049

University of Arizona

9. Mendoza, Erin. Role of p53 in Adaptation to the Tumor Microenvironment .

Degree: 2010, University of Arizona

URL: http://hdl.handle.net/10150/204113

► Tumors cells grow in nutrient and oxygen-deprived microenvironments and adapt to the suboptimal growth conditions by altering their metabolic pathways. The adaptation process commonly creates… (more)

▼ Tumors cells grow in nutrient and oxygen-deprived microenvironments and adapt to the suboptimal growth conditions by altering their metabolic pathways. The adaptation process commonly creates a tumor phenotype of high glycolytic potential and aggressive growth characteristics which facilitate metastasis and confer resistance to radiation and chemotherapy. Understanding the mechanisms that allow tumors to adapt and survive in their microenvironment is crucial to cancer prevention and control. It was hypothesized that the tumor microenvironment would induce signaling and enzymatic changes, which if manipulated could improve treatment outcome. The results presented here demonstrate that exposure of tumor cells to chronic low pH or hypoxic conditions induced signaling cascades and altered enzyme profiles which resulted in a pro-survival phenotype. Three key adaptation events were observed and included 1) the up regulation of the metabolic stress and glycolytic proteins AMP-activated protein kinase (AMPK) and 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (PFKFB3), respectfully. 2) The upregulation of p53 and 3) changes in the ratios of the bioreductive enzymes were also found to be important in the adaptation. The tumor suppressor p53 played a central role in adaptation because it induced the transcription of anti-glycolytic proteins to control glycolysis and minimize tumor cell acidosis. The ratio of bioreductive enzymes was also altered by changes to the microenvironment. Hypoxia had the greatest effect on protein levels and caused a decrease in the ratio of NAD(P)H:quinone oxidoreductase 1 (NQO1): cytochrome p450 reductase. The increase in cytochrome p450 reductase, a one electron bioreduction enzyme, has been shown to increase toxicity of bioreductive drugs in hypoxic tumors. Micronutrients also had an effect on p53 homeostasis because increasing NQO1 activity by riboflavin supplementation induced a p53-stabilizing effect by enhancing binding of p53 to NQO1, protecting the tumor suppressor from degradation. Taken together, these results indicate the changes that occur in tumor adaptation to the microenvironment require signaling and enzymatic changes that work in concert to regulate metabolism and apoptosis. Many of these changes present therapeutic targets that could be exploited to enhance therapy or prevent adaptation and subsequent tumor growth. Advisors/Committee Members: Burd, Randy M (advisor), Limesand, Kirsten H. (committeemember), Romagnolo, Donato F. (committeemember), Baker, Amanda F. (committeemember), Guerriero, Vince (committeemember).

Subjects/Keywords: Cancer

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APA (6^th Edition):

Mendoza, E. (2010). Role of p53 in Adaptation to the Tumor Microenvironment . (Doctoral Dissertation). University of Arizona. Retrieved from http://hdl.handle.net/10150/204113

Chicago Manual of Style (16^th Edition):

Mendoza, Erin. “Role of p53 in Adaptation to the Tumor Microenvironment .” 2010. Doctoral Dissertation, University of Arizona. Accessed March 05, 2021. http://hdl.handle.net/10150/204113.

MLA Handbook (7^th Edition):

Mendoza, Erin. “Role of p53 in Adaptation to the Tumor Microenvironment .” 2010. Web. 05 Mar 2021.

Vancouver:

Mendoza E. Role of p53 in Adaptation to the Tumor Microenvironment . [Internet] [Doctoral dissertation]. University of Arizona; 2010. [cited 2021 Mar 05]. Available from: http://hdl.handle.net/10150/204113.

Council of Science Editors:

Mendoza E. Role of p53 in Adaptation to the Tumor Microenvironment . [Doctoral Dissertation]. University of Arizona; 2010. Available from: http://hdl.handle.net/10150/204113

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