Medicine and Health Sciences Commons^™

The Genetic Associations Of Circadian Rhythm And Sleep Disorder Traits With Risk Of Monoclonal Gammopathy Of Undetermined Significance And Multiple Myeloma, Brittany Crawford

Theses and Dissertations

Background: Circadian rhythm disruption and sleep have been widely studied for their roles in immunity and cancer development. Evidence for an association of circadian rhythm and sleep traits with multiple myeloma (MM) risk is inconclusive. No studies have investigated these traits in relation to monoclonal gammopathy of undetermined significance (MGUS). Given that MGUS precedes almost all MM cases, investigating sleep and circadian rhythm in relation to both MM and MGUS is necessary. The purpose of this dissertation was to explore the genetic influences of circadian rhythm and sleep traits on the risk of MGUS and MM. Methods: Data were leveraged …

Mediator Kinase Inhibitors For Breast Cancer Therapy, Xiaokai Ding

Theses and Dissertations

Breast cancers (BrCa) that overexpress oncogenic tyrosine kinase receptor HER2 are treated with HER2-targeting antibodies (such as trastuzumab) or small-molecule kinase inhibitors (such as lapatinib). However, most patients with metastatic HER2+ BrCa have intrinsic resistance and nearly all eventually become resistant to HER2-targeting therapy. Resistance to HER2-targeting drugs frequently involves transcriptional reprogramming associated with constitutive activation of different signaling pathways. We have investigated the role of CDK8/19 Mediator kinase, a regulator of transcriptional reprogramming, in the response of HER2+ BrCa to HER2-targeting drugs. Selective CDK8/19 inhibitors (senexin B and SNX631) showed synergistic interactions with lapatinib and trastuzumab in a panel …

The Development Of Novel Cdk8 And Cdk19 Inhibitors And Degraders As Potential Anti-Cancer Agents, Li Zhang

Theses and Dissertations

CDK8 and its homolog CDK19 are essential for transcription regulation and their dysregulation has been identified in numerous diseases, especially in cancers. CDK8 and CDK19 have been implicated in cancer development through their kinase activity and kinase independent functions. Despite the existing CDK8/19 inhibitors, there is still a need to develop novel CDK8/19 inhibitors with improved potency and PK profile. It is also necessary to develop CDK8/19 degraders that are able to eliminate the kinase-independent functions. Although two CDK8-degrading PROteolysis Activating Chimeras (PROTACs) have been reported, they have limited CDK8 degradation efficacy and no effect on CDK19. PROTACs with improved …

A Multilevel And Spatial Analysis Of Oral And Pharyngeal Cancer In South Carolina, Deborah M. Hurley

Theses and Dissertations

Objective: Disparities in the distribution of oral and pharyngeal cancer exist worldwide. This is also true in the United States and in South Carolina. Differences exist in oral and pharyngeal cancer stage and survival by race and sex, with higher incidence rates for Whites but higher proportions of late-stage cancer and lower survival for Blacks. This study was conducted to evaluate whether any differences exist in the spatial distribution of oral and pharyngeal cancer stage at diagnosis and survival, and to evaluate the association of income inequality, material deprivation and other measures of social determinants of health (contextual risk factors) …

Design And Synthesis Of Macrocyclic Peptide Braf-Wt Dimerization Inhibitors For The Treatment Of Metastatic Melanoma, Chad Mulloy Beneker

Theses and Dissertations

In cases of metastatic melanoma, BRAF is frequently mutated to the V600E oncoprotein causing uncontrolled cell proliferation driven by the MAPK-ERK pathway. There are several BRAF inhibitors, such as vemurafenib, which are FDA approved, but patients treated with these Type-I kinase inhibitors frequently observe relapse under mutant RAS and BRAF-wt conditions due to paradoxical activation. The mechanism of this resistance occurs through binding of the inhibitor to BRAF-wt initiating conformational changes which leads to BRAF dimerization. Once in the dimerized state, the inhibited monomer induces allosteric transactivation of the second monomer. This drug-induced activation of BRAF in cells with mutant …

Dietary Advanced Glycation End-Products (Ages) And Breast Cancer Risk And Survival, Omonefe Opeyemi Omofuma

Theses and Dissertations

Introduction: Advanced glycation end-products (AGEs) are implicated in the pathogenesis of chronic diseases including cancer. AGEs are produced endogenously and are also consumed from foods. High amounts of AGEs are found in animal products and processed foods, and AGE formation is accelerated during cooking at high temperatures. Using data from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), we assigned and quantified NƐ-carboxymethyl-lysine (CML)-AGE content in food and investigated the association between dietary AGE intake and breast cancer (BrCa) risk. We assessed whether the risk was modified by race/ethnicity, obesity status, fruit and vegetable intake, BrCa invasiveness …

The Regulation Of Skeletal Muscle Fatigue During The Progression Of Cancer Cachexia, Brandon N. Vanderveen

Theses and Dissertations

Cachexia is the unintentional loss of body weight secondary to chronic disease and is prevalent is roughly 50% of cancer patients. The loss of body weight and skeletal muscle mass is reduced functional capacity associated with reduced life quality. The etiology of cachexia is multimodal and complex; however, cachexia has been linked to several systemic (e.g. chronic inflammation, hypogonadism, anemia, insulin resistance) and behavioral (e.g. anorexia, inactivity) changes that can compound to accelerate muscle mass and body weight loss. While several inflammatory cytokines are associated with cachexia’s disease progression, our laboratory has established that Interleukin-6 (IL-6) is a key regulator …

Psychometric Evaluation Of Lung Cancer Stigma Among Lung Cancer Survivors In South Carolina, Lisa A. Webb

Theses and Dissertations

Background: Despite the improved screening and treatment modalities, lung cancer is the second leading cause of cancer and accounts for 27% of all cancer deaths in the United States. Survivors of lung cancer experience physical, social, and particularly psychological challenges. Lung cancer stigma is a formidable challenge for survivors of lung cancer that complicates their physical, psychological and social well-being.

The Cataldo Lung Cancer Stigma Scale is the first instrument adapted to measure lung cancer stigma. This instrument was adapted from Berger’s HIV Stigma Scale. HIV stigma and lung cancer stigma share similarities. These health-related stigmas reflect behaviors that …

The Role Of Cdk8 In Metastatic Growth Of Colon Cancer, Jiaxin Liang

Theses and Dissertations

Unresectable hepatic metastases of colon cancer poorly respond to existing therapies and are a major cause of colon cancer lethality. Transcription- regulating Mediator kinase CDK8, an early clinical stage drug target, is amplified or overexpressed in many colon cancers and CDK8 expression correlates with shorter patient survival. Here we show that CDK8 inhibition does not generally suppress proliferation of CDK8-overexpressing colon cancer cells but nevertheless CDK8 knockdown by shRNA or CDK8 kinase inhibition by a selective small-molecule drug candidate suppresses metastatic growth of mouse and human colon cancer cells in the liver. This effect is due at least in part …

Spiritual Care In Cancer Genetic Counseling: Patient Perceptions Of Methods, Christopher Michael Spencer

Theses and Dissertations

The integration of spirituality into medical care is a growing area of debate among professionals, involving a delicate balance between serving patients who may benefit from this without alienating those who would not. To date, little research has targeted spirituality in cancer genetic counseling, particularly concerning the various methods a genetic counselor can use to address spirituality with their patients. A paper questionnaire was created and distributed to patients following their cancer genetic counseling appointments to gain insight on their perception of these methods. Fifty-two participants completed this questionnaire. The eight different spiritual integration methods presented each showed positive responses …

Association Between Diabetes And Cancer In Indian And Us Populations Using Longitudinal Study Design, Shraddha S. Vyas

Theses and Dissertations

Background: There is growing evidence of association between diabetes and cancer. No studies have been conducted in India evaluating this association. With the current epidemiologic, nutritional and economic transition in India, it becomes extremely important to examine this association in an Indian population. Additionally, difference in association exists based on different cancer subtypes. Research has shown that diabetes is associated with an increased risk of colorectal cancer. However most of these studies suggest detection bias to be one of the probable reasons for this association. Additionally, the common risk factors shared by both these conditions are considered to one of …

Effects Of A Mindfulness Based Intervention On Diurnal Cortisol In Cancer Survivors, Susannah Small

Theses and Dissertations

Background. There are approximately 15.5 million individuals alive today in the U.S. with a personal history of cancer. For this large and growing population, ill effects associated with cancer diagnosis and treatment include both physical and psychosocial symptoms adversely affecting quality of life. One low-risk alternative to conventional pharmaceutical use in treating these symptoms is mindfulness practice. Research on self-reported measures provides strong evidence that this type of intervention improves quality of life for cancer survivors, but evidence of impact on objective measures is limited. Cortisol, the body’s primary stress hormone, is one relatively easy to measure indicator that …

Re-Contacting Cancer Genetic Counseling Patients: Expectations Of Patients And Physicians, Zoe Elizabeth Siegel

Theses and Dissertations

The landscape of cancer genetic counseling and testing is rapidly evolving. Genetic testing technology is improving, management guidelines are evolving, and genetic testing options are expanding. These frequent updates to the components of cancer genetics have increased the complexity of managing patient care over time. In particular, this raises questions on the duty to re-contact patients as new information becomes available. This study explored healthcare providers’ duty to re-contact through the interests and expectations of patients, including which circumstances warrant re-contacting, which healthcare provider is responsible for re-contacting the patient, and the preferred method of re-contacting. Physicians’ opinions on whether …

Stimuli Responsive Nanoparticle For Cancer Targeted Therapy, Huacheng He

Theses and Dissertations

Nanoparticle is the particle with a size in the range from several nanometers to hundreds of nanometers. It has been extensively used for cancer diagnosis and therapy. However, it is still a great challenge to fabricate nanoparticles with spatiotemporally controllable delivery of anticancer drugs to tumors and with high therapeutic efficacy. This thesis mainly focuses on the development of stimuli responsive nanoparticles for cancer targeted therapy. These nanoparticles either response to internal stimuli such as pH and redox potential or external stimuli like temperature and light could effectively target tumors and control the release of anticancer drugs there to improve …

Multifunctional Nanocarriers For Cancer Therapy, Bei Cheng

Theses and Dissertations

Cancer is one of the leading causes of human mortality and mortality in all diseases. There has been a boost in developing nanocarrier-based therapies for treating cancer or other diseases during the past decade. One of the major advantages about nanocarrier (with the size range from 1-1000 nm) lies in its ability to specifically target tumor and maximize drug accumulation in tumor foci through the enhanced permeability and retention effect. Advancement in nanotechnology has opened a new paradigm in pharmaceutical field. But new challenges have to be overcome in order to fully exploit the technology and improve safety in clinical …

Design And Development Of A Novel Class Of Cell Cycle Cdk Inhibitors Targeting The Cyclin Binding Groove Utilizing The Replace Strategy, Padmavathy Nandha Premnath

Theses and Dissertations

Inhibition of CDK2 activity in G1 and S phases of the cell cycle can promote selective apoptosis of cancer cells through the E2F1 pathway. Currently available CDK inhibitors target the ATP binding pocket and result in lack of specificity for the cell cycle vs. the transcriptional CDKs. It has been shown that a peptide HAKRRLIF derived from the tumor suppressor p21 binds to the cyclin binding groove (CBG) and selectively inhibits cell cycle CDKs (CDK2/Cyclin A, CDK2/Cyclin E and CDK4/Cyclin D). The CBG is unique to cell cycle CDKs hence targeting this site avoids the inhibition of transcriptional CDKs can …

Role Of Chronic Inflammation On Liver Function During Cachexia Progression In The ApcMin/+ Mouse Model, Aditi Narsale

Theses and Dissertations

Cachexia is a multifactorial syndrome that manifests during the advanced stage of chronic diseases and is characterized by a progressive loss of body mass sustained by underlying inflammation. The ApcMin/+ mouse is an established model of cachexia that exhibits a gradual loss of body mass correlating with increasing tumor burden and plasma IL – 6 levels. Moreover it also mimics other secondary characteristics observed in cachectic patients like splenomegaly, elevated plasma endotoxin levels, gut barrier dysfunction, hypogonadism and an overall hypermetabolic state. Liver controls the energy metabolism in the body by regulating glucose and lipid metabolism, glycogen storage, filtration of …

Role Of Micro Rna 148/152 Family In Cancer Progression, Anusha Chaparala

Theses and Dissertations

Micro RNA are small single stranded RNA that regulate the expression of various genes. MiRNA guide the mRNA disintegrating RISC complex to the complimentary sequence in the target mRNA. Each micro RNA has multiple targets and can play a different biological role depending on the population of targets at the particular stage of the cell or a physiological state. Several miRNA show elevated or decreased levels of expression in various cancers because of their role in tumor initiation and progression. MiRNA belonging to mir148/152 family are examples of such MicroRNA. This family includes miR148a, miR148b and miR152. MiR148a and miR152 …