Medical Specialties Commons^™

E3 Ligase Identified By Differential Display (Edd) Enhances Cell Survival And Cisplatin Resistance In Epithelial Ovarian Cancer And Oral Squamous Cell Carcinoma, Amber Thompson Bradley

MUSC Theses and Dissertations

EDD (E3-ubiquitin ligase identified by Differential Display) is an E3 ubiquitin ligase that is overexpressed in ovarian cancer, but is rare in benign and borderline tumors. EDD is also overexpressed in recurrent, platinum-resistant ovarian cancers and is associated with a two-fold increased risk of disease recurrence and death in ovarian cancer patients, suggesting a role in tumor survival and/or platinum resistance. EDD knockdown by siRNA induced apoptosis in A2780ip2, OVCAR5, and ES-2 ovarian cancer cells, correlating with a loss of the anti-apoptotic protein Mcl-1 through a GSK-3β-independent mechanism. Transient knockdown of EDD or Mcl-1 induced comparable levels of apoptosis in …

Beta-Alanine Suppresses Malignant Breast Epithelial Cell Aggressiveness Through Alterations In Metabolism And Cellular Acidity In Vitro, Roger A. Vaughan, Nicholas P. Gannon, Randi Garcia-Smith, Yamhilette Licon-Munoz, Miguel A. Barberena, Marco Bisoffi, Kristina A. Trujillo

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Background: Deregulated energetics is a property of most cancer cells. This phenomenon, known as the Warburg Effect or aerobic glycolysis, is characterized by increased glucose uptake, lactate export and extracellular acidification, even in the presence of oxygen. beta-alanine is a non-essential amino acid that has previously been shown to be metabolized into carnosine, which functions as an intracellular buffer. Because of this buffering capacity, we investigated the effects of beta-alanine on the metabolic cancerous phenotype.

Methods: Non-malignant MCF-10a and malignant MCF-7 breast epithelial cells were treated with beta-alanine at 100 mM for 24 hours. Aerobic glycolysis was quantified …

18 F-Fluorothymidine Uptake In Follicular Lymphoma And Error-Prone Dna Repair, Marielle J. Wondergem, Ken Herrmann, Sergei Syrbu, Josee M. Zijlstra, Nikie Hoetjes, Otto S. Hoekstra, Saskia Agm Cillessen, Laura M. Mosenbergen, Andreas K. Buck, Julie M. Vose, Malik E. Juweid

Journal Articles: Oncology and Hematology

BACKGROUND:

We observed a disproportional 18 F-fluorothymidine (F-FLT) uptake in follicular lymphoma (FL) relative to its low cell proliferation. We tested the hypothesis that the 'excess' uptake of 18 F-FLT in FL is related to error-prone DNA repair and investigated whether this also contributes to 18 F-FLT uptake in diffuse large B cell lymphoma (DLBCL).

METHODS:

We performed immunohistochemical stainings to assess the pure DNA replication marker MIB-1 as well as markers of both DNA replication and repair like PCNA, TK-1 and RPA1 on lymph node biopsies of 27 FLs and 35 DLBCLs. In 7 FL and 15 DLBCL patients, …

Breast Cancer Survivorship In African American Women, Michelle Arda Mollica

MUSC Theses and Dissertations

With advances in screening, diagnostic capabilities, and treatments, the amount of breast cancer survivors continues to grow. African American (AA) breast cancer survivors (BCS) are a particularly vulnerable group, who experience persistent disparities in outcomes, information, and support post primary cancer treatment. Peer navigation (PN) in AA BCS could be one strategy to increase quality of life and follow-up care after treatment, though research on quality of life and PN in this population is limited. This dissertation first examines factors contributing to quality of life in AA BCS, utilizing the Quality of Life Model Applied to Cancer Survivors. Next, the …

Enhancing The Efficacy Of Enzalutamide By Inhibition Of Sphingosine Kinase 2 To Target Inflammation And Tumor Proliferation, Heather Venant

MUSC Theses and Dissertations

Prostate cancer is the second leading cause of cancer death in American men. The interaction of androgen with its receptor (AR) is one of the major pathways that contributes to the progression of prostate cancer. As a result, hormone deprivation is a major strategy for prostate cancer treatment, but the emergence of castration resistant prostate cancer (CRPC) is a major clinical problem. Recently, the novel AR inhibitor, enzalutamide, demonstrated improved survival in men with metastatic CRPC by 4.8 months (13.8 vs 18.4 months in placebo vs treated groups) (18). While these results are encouraging, they also indicate that there is …

Dual-Specificity Phosphatase-1 Regulates The Inflammatory Milieu In Head And Neck Squamous Cell Carcinoma, Xiaoyi Zhang

MUSC Theses and Dissertations

Head and neck cancer accounts for approximately 6% of diagnosed malignancies in the United States, with an estimated 35,000 incidences and over 7,000 deaths every year. Head and neck squamous cell carcinoma (HNSCC) comprises the majority of head and neck cancers, with a worldwide incidence of more than 500,000 cases. Head and neck cancer patients often present in advanced stages of disease, and despite ongoing research, survival rates remain lower than other more common malignancies. Cytokines and pro-inflammatory factors have been shown to have a critical role in the various steps of malignant transformation, including tumor growth, survival, invasion, angiogenesis, …

Investigating The Role Of Dachshund Homolog 1 (Dach1) And Mir-200b In Group 4 Medulloblastoma Pathogenesis, Courtney George

Theses : Honours

Medulloblastoma is the most common malignant childhood brain tumour, and the most significant cause of childhood cancer-related mortality. Recently four core molecular medulloblastoma sub-groups have been identified, with distinct pathogenesis and responses to therapies. Current therapies, do not account for this molecular variation, and many patients may receive inappropriate treatment. To address this, targeted therapies for each molecular sub-group would be ideal. Unfortunately, for the more aggressive Group 3 and Group 4 subgroups, the underlying mechanisms of pathogenesis remain poorly understood. The current challenge is to identify the key tumour suppressors or oncogenes involved in Group 3 and Group 4 …

Functional Genomic And Proteomic Analysis Of Highly Drug Resistant Chronic Myeloid Leukemia, Derrick Matthew Oaxaca

Open Access Theses & Dissertations

Chronic Myeloid Leukemia (CML) has served as a model for how cancer can be selectively targeted with advanced forms of chemotherapies known as kinase inhibitors. Such new therapies have significantly altered the field of oncology and have led to monumental increases in both survival rates and quality of life for cancer patients. However, approximately one-third of CML patients will go on to develop drug resistance against major kinase inhibitors. Along with this, other cancers are showing increased incidences of drug resistance. Understanding how these cancers, such as CML, overcome drug sensitivity is of major importance within the clinic. To predict …

Molecular Studies On The Anti-Tumor Effects Of Metal-Based Complexes: Involvement Of The Ubiquitin-Proteasome And Apoptotic Pathways, Sara M. Schmitt

Wayne State University Dissertations

The ubiquitin-proteasome pathway is crucial to normal cellular function, and as such, has been extensively investigated as a potential target for cancer therapeutics. Many compounds have been tested for their proteasome inhibitory ability, including various small peptide aldehydes, and, following the success of cisplatin, several metal-containing complexes. The efficacy of these compounds in preclinical studies ultimately resulted in the development and approval of the first-in-class proteasome inhibitor bortezomib, the use of which, unfortunately, has been hindered by toxicity and resistance. These limitations have led to a massive push toward designing and developing new, less toxic proteasome inhibitors for clinical use. …

Combating Resistance To Epidermal Growth Factor Recpetor Inhibitors In Triple Negative Breast Cancer, Julie Marie Madden

Wayne State University Dissertations

Triple negative breast cancer (TNBC) patients suffer from a highly malignant and aggressive cancer that lacks an effective targeted therapeutic. Although many TNBCs, both in vitro and in vivo, have increased expression of epidermal growth factor receptor (EGFR), EGFR targeted inhibitors, such as gefitinib (GEF), have yet to demonstrate efficacy. Using mass spectrometry to identify pathways that remain activated in the presence of GEF, we found that components of the mTOR signaling pathway remain phosphorylated. While inhibiting mTOR with temsirolimus (TEM) decreased mTOR signaling, EGFR signaling pathways remained activated and the TNBC cell lines continued to proliferate. However, dual treatment …

Pathway Profiling Of Replicative And Induced Senescence, Maggie Purcell

Wayne State University Dissertations

Senescence is a permanent withdrawal from cell cycle that occurs naturally in cells in response to the shortening of telomeres. This natural "clock" serves to limit the number of cell divisions and therefore protects the cell from potentially carcinogenic mutations. However, senescence also occurs in response to external stresses to the cell, which is known as induced senescence. This study compares the mechanisms of natural senescence, a response to the shortening of telomeres during replication, with induced senescence by using various drugs to induce senescence: 5-aza-2-deoxycytidine (a demethylating agent), Adriamycin (a chemotherapeutic drug), and H2O2 (an agent causing oxidative stress). …

The Impact Of Prostate Cancer On Survivors' Sense Of Meaning In Life, Carol Lynn Brady

Walden Dissertations and Doctoral Studies

Research has shown that meaning in life is a universal human need, regardless of cultural identity or education. This research study investigated how the encounter with prostate cancer impacted men's sense of well-being and what they considered meaningful in life. An interpretative phenomenological research design was used because of its descriptive nature and its focus on the individual's perspective. The sample included 6 men between the ages of 18 and 65 who had been out of treatment for 1 year. Participants completed essays about their perceptions and experiences over 3 periods of time: before diagnosis, during treatment, and as survivors. …

Regulation And Targeting Of Fyn In Human Cutaneous Squamous Cell Carcinoma, Sarah Fenton

Dissertations

Fyn, a member of the Src family kinases, is an oncogene in murine epidermis and is associated with cell-cell adhesion turnover and migration. Introduction of active H-Ras(G12V) into the HaCaT human keratinocyte cell line resulted in upregulation of FYN mRNA (200-fold) and protein, but did not increase the expression of other SFKs. We identified two nucleotides 74 bases upstream of the human FYN gene transcription start site as necessary for FYN upregulation in HaCaT-Ras cells. Further studies identified Lef-1 as the transcription factor most likely binding to this site and mediating FYN upregulation.

Transduction of active Ras or Fyn was …

Let-7 Microrna-Binding-Site Polymorphism In The 3′Utr Of Kras And Colorectal Cancer Outcome: A Systematic Review And Meta-Analysis, Scott M. Langevin, Brock C. Christensen

Dartmouth Scholarship

There is a small but growing body of literature regarding the predictive utility of a Let-7 microRNA-binding-site polymorphism in the 30 -untranslated region (UTR) of KRAS (KRAS-LCS6) for colorectal cancer outcome, although the results are conflicting. We performed a review and meta-analysis in an attempt to better clarify this relationship. A PubMed search was conducted to identify all studies reporting on KRAS let-7 microRNA-binding site polymorphism (LCS6; rs61764370) and colorectal cancer outcome. Hazard ratios (HR) and corresponding 95% confidence intervals (CI) were extracted or estimated from each manuscript. Log HRs and log CIs were combined across studies using the inverse-variance …

Analysis Of The Role Of Astrocyte Elevated Gene-1 In Normal Liver Physiology And In The Onset And Progression Of Hepatocellular Carcinoma, Chadia L. Robertson

Theses and Dissertations

First identified over a decade ago, Astrocyte Elevated Gene-1 (AEG-1) has been studied extensively due to early reports of its overexpression in various cancer cell lines. Research groups all over the globe including our own have since identified AEG-1 overexpression in cancers of diverse lineages including cancers of the liver, colon, skin, prostate, breast, lung, esophagus, neurons and neuronal glia as compared to matched normal tissue. A comprehensive and convincing body of data currently points to AEG-1 as an essential component, critical to the progression and perhaps onset of cancer. AEG-1 is a potent activator of multiple pro-tumorigenic signal transduction …

Adaptive Radiation Therapy For Lung Cancer, Christian W. Dial

Theses and Dissertations

Prognosis for lung cancer patients remains poor. For those receiving radiation therapy, local control and survival have been shown to improve with increased doses; however, deliverable dose is often limited by associated toxicity. Therefore, methods that reduce dose to normal tissues and allow isotoxic escalation are desirable. Adaptive radiation therapy seeks to improve treatment by modifying the initial plan throughout delivery, and has been shown to decrease normal tissue dose. Studies to date suggest a trend of increasing benefit with increases in replanning frequency; however, replanning is costly in terms of workload and past studies implement at most weekly adaptation. …

E5501: Phase Ii Study Of Topotecan Sequenced With Etoposide/Cisplatin, And Irinotecan/Cisplatin Sequenced With Etoposide For Extensive-Stage Small-Cell Lung Cancer., Taofeek K. Owonikoko, Joseph Aisner, Xin Victoria Wang, Suzanne E. Dahlberg, Eric H. Rubin, Suresh S. Ramalingam, Murugesan Gounder, Paul Gregory Rausch, Rita S. Axelrod, Md, Joan H. Schiller

Department of Medical Oncology Faculty Papers

PURPOSE: Sequence-dependent improved efficacy of topoisomerase I followed by topoisomerase 2 inhibitors was assessed in a randomized phase II study in extensive-stage small-cell lung cancer (SCLC).

METHODS: Patients with previously untreated extensive-stage SCLC with measurable disease, ECOG performance status of 0-3 and stable brain metastases were eligible. Arm A consisted of topotecan (0.75 mg/m(2)) on days 1, 2 and 3, etoposide (70 mg/m(2)) and cisplatin (20 mg/m(2)) (PET) on days 8, 9 and 10 in a 3-week cycle. Arm B consisted of irinotecan (50 mg/m(2)) and cisplatin (20 mg/m(2)) on days 1 and 8 followed by etoposide (85 mg/m(2) PO …

A Potential Mechanism For Extracellular Matrix Induction Of Breast Cancer Cell Normality, Robert D. Bruno, Gilbert H. Smith

School of Medical Diagnostics & Translational Sciences Publications

Extracellular matrix proteins from embryonic mesenchyme have a normalizing effect on cancer cells in vitro and slow tumor growth in vivo. This concept is suggestive of a new method for controlling the growth and spread of existing cancer cells in situ and indicates the possibility that extracellular proteins and/or embryonic mesenchymal fibroblasts may represent a fertile subject for study of new anti-cancer treatments.

Choroidal Metastasis From Leiomyosarcoma In Two Cases, Eric Feinstein, Swathi Kaliki, Carol L Shields, Hormoz Ehya, Jerry A Shields

Wills Eye Hospital Papers

Leiomyosarcoma is a malignant tumor of mesenchymal cells and is the most common soft-tissue sarcoma. Leiomyosarcoma is a notably rare tumor in the ophthalmic region and can be of primary, secondary or metastatic origin. To the best of our knowledge, there has only been one published case of leiomyosarcoma metastasis to the choroid. In this case study, we report two cases of primary leiomyosarcoma with metastasis to the choroid of the eye. Both cases displayed systemic metastasis and showed response to high dose plaque radiotherapy. Despite its prevalence as the leading form of sarcoma, leiomyosarcoma rarely metastasizes to the ocular …

Automated Classification Of Malignant Melanoma Based On Detection Of Atypical Pigment Network In Dermoscopy Images Of Skin Lesions, Nabin K. Mishra

Doctoral Dissertations

“Melanoma causes more deaths than any other form of skin cancer. Early melanoma detection is important to prevent progression to a more deadly stage. Automated computer-based identification of melanoma from dermoscopic images of skin lesions is the most efficient method in early diagnosis. An automated melanoma identification system must include multiple steps, involving lesion segmentation, feature extraction, feature combination and classification. In this research, a classifier-based approach for automatically selecting a lesion border mask for segmentation of dermoscopic skin lesion images is presented. A logistic regression based model selects a single lesion border mask from multiple border masks generated by …

Novel Microwave Applicators Based On Zero-Order Mode Resonance For Hyperthermia Treatment Of Cancer, David Vrba, Jan Vrba, Paul R. Stauffer

Department of Radiation Oncology Faculty Papers

In this paper, three novel microwave applicator prototypes based on zero-order mode resonators are proposed for use in hyperthermia treatment of cancer. The ability of all three applicators to homogenously irradiate muscle tissue-equivalent phantoms is demonstrated with results of numerical simulations, and relative performance of the applicators is compared.

The Symptom Experience Of Patients Receiving Epidermal Growth Factor Receptor Inhibitors, Josephine Ann Howard-Ruben

Dissertations

This study explored the symptom experience of patients receiving epidermal growth factor receptor inhibitors (EGFRIs) for breast, colon, head and neck, and colon cancer. EGFRIs are targeted therapies used at various points along the treatment continuum for these solid tumors, and may be first, second or third-line agents which can be used as single agents or in combination with other therapies. The most common side effect of these agents include dermatologic effects, such as rashes, hair, and nail changes, but they can also contribute to other side effects such as fatigue, anxiety and diarrhea. Most previous work has addressed the …

Reevaluation Of The Aapm Tg-43 Brachytherapy Dosimetry Parameters For An 125I Seed, And The Influence Of Eye Plaque Design On Dose Distributions And Dose-Volume Histograms, Prakash Aryal

Theses and Dissertations--Physics and Astronomy

The TG-43 dosimetry parameters of the Advantage^{TM 125}I model IAI-125A brachytherapy seed were studied. An investigation using modern MCNP radiation transport code with updated cross-section libraries was performed. Twelve different simulation conditions were studied for a single seed by varying the coating thickness, mass density, photon energy spectrum and cross-section library. The dose rate was found to be 6.3% lower at 1 cm in comparison to published results. New TG-43 dosimetry parameters are proposed.

The dose distribution for a brachytherapy eye plaque, model EP917, was investigated, including the effects of collimation from high-Z slots. Dose distributions for …

Novel Therapeutic Strategies For Pancreatic Cancer, Bridget A. Quinn

Theses and Dissertations

Pancreatic cancer is a devastating disease that leaves patients with a very poor prognosis and few therapeutic options. Many of the treatment options available are the same that have been used for almost 2 decades. There is a dire need for both novel treatments for this disease as well as novel strategies of treatment. This body of work will introduce and provide evidence in support of a novel combination therapy for pancreatic cancer treatment, a novel strategy of modifying currently used chemotherapeutics for pancreatic cancer therapy, and a novel transgenic preclinical mouse model of pancreatic cancer. Sabutoclax, an antagonist of …

Mda-9/Syntenin: From Glioblastoma Pathogenesis To Targeted Therapy, Timothy P. Kegelman

Theses and Dissertations

The most common malignant glioma, glioblastoma multiforme (GBM), remains an intractable tumor despite advances in therapy. Its proclivity to infiltrate surrounding brain tissue contributes greatly to its treatment failure and the grim prognosis of patients. Radiation is a staple in modern therapeutic regimens, though cells surviving radiation become more aggressive and invasive. Consequently, it is imperative to define further the cellular mechanisms that control GBM invasion and identify promising novel therapeutic targets. Melanoma differentiation associated gene-9 (MDA-9/Syntenin) is a highly conserved PDZ domain-containing scaffolding protein that promotes invasion and metastasis in human melanoma models. We show that MDA-9/Syntenin is robustly …

Making Space For Dying: Portraits Of Living With Dying, Elise Lark

Antioch University Dissertations & Theses

In Making Space for Dying: Portraits of Living with Dying, I describe the everyday lived experience of dying and the care culture within freestanding, community-based, end-of-life residences (CBEOLR) utilizing portraiture and arts-based research. I craft four case studies into “portraits,” based on interviews, on-site visits, up-close observation, and field notes. In the person-centered portraits, I reveal the inner landscape of two terminally ill women, with data represented in poetry. In the place-centered portraits, I “map” the social topography of two CBEOLRs to illustrate how lives and care of the dying are emplaced, from the perspectives of community leaders, …

Role Of Physical Exercise In Reducing Depression And Improving Mental Health In Cancer Survivors, Gregory Levin

Theses: Doctorates and Masters

Cancer survivors are more than twice as likely as the general population to suffer the debilitating effects of depression. This comorbid condition is associated with several negative consequences, such as reduction in compliance with cancer treatments, and hastened mortality. Recent research has examined the therapeutic effect of exercise on depression and reported excellent results of similar magnitude to those achieved with pharmacotherapy or psychological intervention. However, no research, to date, has examined the effectiveness of exercise on reducing depression in depressed cancer survivors. In order to address this important question this thesis reviewed previous literature in the area of cancer …

Mediastinal Synovial Sarcoma., Niaz Hussain Soomro, Sanaullah Junejo, Aneeqa Ahsan Zafar, Shirin Siddiqi, Ghulam H

Department of Medicine

The mediastinum is an uncommon site of synovial sarcoma which is a rare soft tissue malignancy. An 18 year old boy was admitted for right sided chest pain since one year. Based on the CT scan chest findings, tru-cut biopsy of the mass was performed and histopathology initially reported as neurofibroma. The tumor was excised via posterolateral thoracotomy and excisional biopsy established the diagnosis of primary synovial sarcoma arising from the mediastinum. Patient was started on adjuvant chemotherapy at the oncologist tumor board’s recommendation and he received 6 cycles of adriamycin and ifosfamide. At last follow up he is free …

Burkitt Lymphoma Presenting As Left Lateral Rectus Palsy, Daniel Tseytlin Do, Usman Shah Md

Department of Medicine

No abstract provided.

Effect Of L-Type Calcium Channel Blocker (Amlodipine) On Myocardial Iron Deposition In Patients With Thalassaemia With Moderate-To-Severe Myocardial Iron Deposition: Protocol For A Randomised, Controlled Trial, Amarah Shakoor, Maaman Zahoor, Alina Sadaf, Najveen Alvi, Zehra Fadoo, Arjumand Rizvi, Farheen Quadri, Fateh Ali Tipoo, Mohammad Khurshid, Zaffar Sajjad, Steven Colan, Babar S Hasan

Department of Paediatrics and Child Health

Introduction: Sideroblastic cardiomyopathy secondary to repeated blood transfusions is a feared complication in thalassaemia. Control of myocardial iron is thus becoming the cornerstone of thalassaemia management. Recent evidence suggests a role for L-type Ca²⁺ channels in mediating iron uptake by the heart. Blocking the cellular iron uptake through these channels may add to the benefit of therapy to standard chelation in reducing myocardial iron. We aim to determine the efficacy of amlodipine (a calcium channel blocker) as an adjunct to standard aggressive chelation in retarding myocardial iron deposition in thalassaemics with or without cardiomyopathy.
Outcomes: The primary outcome …