Dissertations / Theses on the topic 'Therapeutic modality for cancer'
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1
Pozniak, John. "Systemic Delivery of microRNA as a Therapeutic Modality to Treat Cancer." University of Cincinnati / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1367939186.
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McCarthy, Alexandra Leigh. "A rebellious distemper : a Foucaultian history of breast cancer to 1900." Thesis, Queensland University of Technology, 2005. https://eprints.qut.edu.au/16030/1/Alexandra_McCarthy_Thesis.pdf.
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This dissertation explores some of the conditions of possibility underpinning contemporary breast cancer discourse, which is imbued with harsh moral, social and spiritual nuance. I have therefore explored a set of questions concerned with the past state of things in breast cancer care that laid the foundation for present approaches. I wanted to know how it became possible to speak what we now regard as the only truth about breast cancer. I wanted to understand how this truth was determined; who determined it, and who or what gave them the right to assert that their truth was the only truth. I wanted to acquire insight into the ways that thinking about and managing breast cancer based on this truth came to dominate the post-modern consciousness (rather than other, perhaps equally valid ways). And if it was possible, I wanted to open up a space for thinking differently about breast cancer. Finally, I wanted to test the fit of the ideas of the philosopher-historian, Michel Foucault, to these questions.
Foucault's notions of discontinuity, discipline, the gaze, normalising judgements and to a lesser extent, some aspects of power/knowledge and the ethics of the self are here tested on the surgical archive of breast cancer, which housed the discourse that best represented Western societal beliefs about the disease, and which had been invested by society with the greatest authority in its conception and management. The analytic framework - modes of consciousness - suggested by Foucault provided a coherent structure with which to explore the archive. I found that there are numerous elements in the archive instrumental in cementing the conditions of possibility for breast cancer discourse in our own time. This dissertation demonstrates that, as is the case in the present day, these were based on unstable truths about breast cancer that were a result of a complex of sociocultural and political norms rather than an objective truth.
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McCarthy, Alexandra Leigh. "A Rebellious Distemper: A Foucaultian History of Breast Cancer to 1900." Queensland University of Technology, 2005. http://eprints.qut.edu.au/16030/.
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This dissertation explores some of the conditions of possibility underpinning contemporary breast cancer discourse, which is imbued with harsh moral, social and spiritual nuance. I have therefore explored a set of questions concerned with the past state of things in breast cancer care that laid the foundation for present approaches. I wanted to know how it became possible to speak what we now regard as the only truth about breast cancer. I wanted to understand how this truth was determined; who determined it, and who or what gave them the right to assert that their truth was the only truth. I wanted to acquire insight into the ways that thinking about and managing breast cancer based on this truth came to dominate the post-modern consciousness (rather than other, perhaps equally valid ways). And if it was possible, I wanted to open up a space for thinking differently about breast cancer. Finally, I wanted to test the fit of the ideas of the philosopher-historian, Michel Foucault, to these questions. Foucault's notions of discontinuity, discipline, the gaze, normalising judgements and to a lesser extent, some aspects of power/knowledge and the ethics of the self are here tested on the surgical archive of breast cancer, which housed the discourse that best represented Western societal beliefs about the disease, and which had been invested by society with the greatest authority in its conception and management. The analytic framework - modes of consciousness - suggested by Foucault provided a coherent structure with which to explore the archive. I found that there are numerous elements in the archive instrumental in cementing the conditions of possibility for breast cancer discourse in our own time. This dissertation demonstrates that, as is the case in the present day, these were based on unstable truths about breast cancer that were a result of a complex of sociocultural and political norms rather than an objective truth.
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Walker, Teneille. "Therapeutic Drugs in Cancer." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1722.
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The first study examined the interaction between low doses of the multi-kinase inhibitor sorafenib and the histone deacetylase inhibitor vorinostat in colon cancer cells. Sorafenib and vorinostat synergized to kill HCT116 and SW480 cells. In SW480 cells, sorafenib+vorinostat toxicity correlated with CD95 activation and CD95-stimulated autophagy. Drug lethality in SW480 cells was blocked by knock down of CD95. In SW620 cells that are patient matched to SW480 cells, sorafenib+vorinostat toxicity was significantly reduced that correlated with a lack of CD95 activation and lower expression of ceramide synthase 6 (LASS6). Overexpression of LASS6 in SW620 cells enhanced drug-induced CD95 activation and tumor cell killing, whereas knock down of LASS6 in SW480 cells suppressed CD95 activation. In HCT116 cells, sorafenib+vorinostat did not increase CD95 plasma membrane levels, weakly induced caspase 8 association with CD95, and knock down of CD95 enhanced drug lethality. In HCT116 cells sorafenib+vorinostat treatment caused CD95-dependent autophagy that was a protective signal. Thus, treatment of tumor cells with sorafenib+vorinostat activates CD95 that promotes viability via autophagy or degrades survival via extrinsic or intrinsic pathways. Drug-induced activation of the de novo ceramide synthesis pathway plays a key role in CD95 activation. The second project explores the mechanism by which the combination of 17AAG, an hsp90 inhibitor, and PD184352, a MEK1/2 inhibitor alters survival in colon cancer cells. 17AAG and PD184352 synergized to kill HCT116 and SW480 cells. In HCT116 cells drug-exposure increased CD95 plasma membrane levels In SW620 cells, 17AAG and PD184352 toxicity was significantly reduced that correlated with a lack of CD95 activation and lower expression LASS6. Overexpression of LASS6 in SW620 cells enhanced drug-induced CD95 activation and tumor cell killing. In Mia Paca2 cells, a pancreatic cell line, inhibition of caspase 8 or overexpression of c-FLIP-s suppressed cell killing by PD184352 and 17AAG exposure. Drug lethality in Mia Paca2 cells was blocked by knock down of CD95. Additionally, overexpression of Bcl-xL or knockdown of caspase 9 decreased cell killing in 17AAG and PD184352 combination treatment. Thus, 17AAG+PD184352 exposure activates the extrinsic and intrinsic apoptotic pathways to kill Mia Paca2 cells. This document was created in Microsoft Word 2000.
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Wang, Chao. "Integrative Analysis of Multi-modality Data in Cancer." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429791373.
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Wall, Richard Andrew. "Multi-Modality Endoscopic Imaging for the Detection of Colorectal Cancer." Diss., The University of Arizona, 2013. http://hdl.handle.net/10150/301761.
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Optical coherence tomography (OCT) is an imaging method that is considered the optical analog to ultrasound, using the technique of optical interferometry to construct two-dimensional depth-resolved images of tissue microstructure. With a resolution on the order of 10 μm and a penetration depth of 1-2 mm in highly scattering tissue, fiber optics-coupled OCT is an ideal modality for the inspection of the mouse colon with its miniaturization capabilities. In the present study, the complementary modalities laser-induced fluorescence (LIF), which offers information on the biochemical makeup of the tissue, and surface magnifying chromoendoscopy, which offers high contrast surface visualization, are combined with OCT in endoscopic imaging systems for the greater specificity and sensitivity in the differentiation between normal and neoplastic tissue, and for the visualization of biomarkers which are indicative of early events in colorectal carcinogenesis. Oblique incidence reflectometry (OIR) also offers advantages, allowing the calculation of bulk tissue optical properties for use as a diagnostic tool. The study was broken up into three specific sections. First, a dual-modality OCTLIF imaging system was designed, capable of focusing light over 325-1300 nm using a reflective distal optics design. A dual-modality fluorescence-based SMC-OCT system was then designed and constructed, capable of resolving the stained mucosal crypt structure of the in vivo mouse colon. The SMC-OCT instrument's OIR capabilities were then modeled, as a modified version of the probe was used measure tissue scattering and absorption coefficients.
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Martin, Aditi Pandya. "Therapeutic drugs in cancer and resistance." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1717.
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We investigated the mechanism of toxicity and resistance development of small molecule tyrosine kinase inhibitor lapatinib in HCT 116 colon cancer cells. Lapatinib mediated cell death in HCT 116 cells was caspase independent and involved cytosolic release of apoptosis inducing factor. Treatment of HCT 116 cells with 10µM Lapatinib lead to the outgrowth of lapatinib resistant HCT 116 cells. Our studies show that alterations in the expression and activation of Bcl-2 family proteins allow lapatinib resistant HCT 116 cells to resist cytotoxic effects of lapatinib as well as of other commonly used chemotherapeutic agents. In hepatoma and pancreatic cancer cells, the effects of combining multi-kinase inhibitor sorafenib with histone deacetylase inhibitors (HDACIs) namely, vorinostat and sodium valproate were investigated. It was found that sorafenib synergizes with HDACIs resulting in enhanced cell death compared to death induced by the drugs individually. The mechanism of action of sorafenib and vorinostat combination treatment as well as sorafenib and sodium valproate combined treatment was shown to involve activation of the CD95 death receptor pathway. Alterations in the CD95 pathway can render cancer cells resistant to chemotherapeutic agents. Hence, we combined sorafenib+sodium valproate with a BH-3 domain mimetic named obatoclax (GX-15-070) which resulted in enhanced toxicity to cancer cells. More importantly, knock-down of CD95 (to mimic non-functional CD95 pathway) reduced cell death induced by sorafenib+sodium valproate combined but failed to protect cells from cell death induced by sorafenib+sodium valproate+obatoclax combined. This suggests that combining sorafenib+HDACI with obatoclax may not only enhance toxicity to cancer cells but may also reduce chances of resistance development via alterations in the CD95 pathway. These studies enhance our knowledge of existing treatment strategies for cancer as well as throw light on how current approaches can be improved in order to better diagnose and treat cancer. Understanding mechanisms of drug action as well as resistance development will allow us to combine existing therapies effectively in order best target cancer cells as well as provide us with information that can help us design new cancer treatment strategies.
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Quinn, Bridget A. "Novel Therapeutic Strategies for Pancreatic Cancer." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/4671.
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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 the anti-apoptotic Bcl-2 proteins, and Minocycline, a commonly used antibiotic, show potent synergy when used in combination in both pancreatic cancer cells and in multiple immune-deficient and immune-competent mouse models of pancreatic cancer. Sabutoclax alone is capable of inducing cell cycle arrest and apoptosis in cells and its cytotoxicity is enhanced significantly when combined with Minocycline. This combination results in the loss of Stat3 activation both in vitro and in vivo, which is essential for its toxicity. It also inhibits tumor growth and prolongs survival in the KPC transgenic mouse model of pancreatic cancer. Also presented here are studies that demonstrate efficacy in vivo of modified versions of Gemcitabine and Paclitaxel. These drugs are linked to a peptide that shows specificity for the EphA2 receptor, which is overexpressed on the surface of pancreatic cancer cells and only minimally on normal cells. This peptide results in increased cellular uptake of drug, as it is bypassing its normal mechanism of entry. These normal mechanisms are often dysregulated in cancer, leading to decreased uptake and drug resistance. The use of these modified drugs show significantly increased tumor growth inhibition as compared to the parent drug alone. Finally, we provide data on the characterization of a novel transgenic mouse model of pancreatic cancer. This model, the Pan Met View (PMV) mouse, combines the commonly used KPC transgenic mouse model of pancreatic cancer and a mouse that expresses a Luciferase reporter gene under the control of the cancer-specific promoter, CCN1. Our data shows that double transgenic PMV mice can now be used to follow primary tumor and metastasis development in real time by Bioluminescent imaging (BLI) through disease progression and potentially therapy. This strategy will enhance the use of genetically engineered mouse models (GEMMS) to study cancer initiation and progression with potential to non-invasively monitor therapy. These chapters present novel and exciting data that have the potential to open multiple avenues of translational study and result in significant advances in pancreatic cancer therapy.
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Kurtyka, Courtney A. "Novel Therapeutic Strategies in Lung Cancer." Scholar Commons, 2014. https://scholarcommons.usf.edu/etd/5363.
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Lung cancer is the leading cause of cancer-related death and the second most diagnosed cancer in the United States. Unfortunately, many patients either do not have any common mutations for which there are already targetable agents, or they eventually become resistant to these compounds. As such, there is a high demand for new, effective methods of treating this disease as well as predicting patient prognosis and potential benefit from chemotherapy. In this work, numerous strategies for treating lung cancer are explored.
The first method described here is through the use of a pan-early 2 factor (E2F) inhibitor, HLM006474, which is shown to synergize with paclitaxel in non-small cell lung cancer (NSCLC). Next, we explored the creation and utilization of an E2F signature that is prognostic and predictive of early-stage NSCLC patient benefit from adjuvant chemotherapy (ACT). The third project examined possible targets to enhance sensitivity to cisplatin in NSCLC lacking Kirsten rat sarcoma viral oncogene homolog (KRAS) and epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma receptor tyrosine kinase (ALK) fusions (triple-negative), for which cisplatin is one of the few treatment options. These studies led to the identification of a kinase that is overexpressed in NSCLC and whose knockdown sensitizes cells to platinum agents.
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Young, Jennifer Denise. "Imaging and therapeutic radiotracers for prostate cancer." Thesis, King's College London (University of London), 2018. https://kclpure.kcl.ac.uk/portal/en/theses/imaging-and-therapeutic-radiotracers-for-prostate-cancer(4822a0bb-f8a4-4738-bd61-23bb1b500e8d).html.
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Radiotracers that target glutamate carboxypeptidase II, also known as the prostate specific membrane antigen (GCP(II)/PSMA), have shown exceptional promise for prostate cancer imaging and molecular radiotherapy. A number of bioconjugates have been developed to target GCP(II)/PSMA which utilise the simple and robust targeting motif (Lys-C(O)-Glu) (referred to as PSMA ligand), functionalised with a chelator for radiometal incorporation. This work utilised and evaluated the tris(hydroxypyridinone) (THP) chelator due to the simplicity, speed and selectivity of its radiolabelling with gallium radioisotopes, and its potential to be developed into one-step radiopharmaceutical kits. [68Ga]Ga-THP-PSMA was assessed as a PET imaging agent and [67Ga]Ga-THP-PSMA for molecular radiotherapy due to its Auger electron emissions. The first objective was to synthesise THP-PSMA and assess its radiolabelling with gallium-68. [68Ga]Ga-THP-PSMA with over 95% radiochemical purity was produced at room temperature, and pH 7 in just 5 minutes. A one-step kit was developed, suitable for use with gallium-68 directly from a generator. [68Ga]Ga-THP-PSMA exhibited specific uptake in GCP(II)/PSMA-expressing prostate cancer cells and 50% inhibition of binding at a concentration of 361 ± 60 nM. In vivo PET imaging showed specific uptake in GCP(II)/PSMA-expressing tumours, reaching 5.6 ± 1.2 percentage injected dose per cubic centimetre. Overall, [68Ga]Ga-THP-PSMA had equivalent imaging properties but greatly simplified radiolabelling compared to other [68Ga]Ga-PSMA tracers. Clinical studies were then conducted by collaborators which found that [68Ga]Ga-THP-PSMA could delineate prostate cancer in both initial staging and biochemical recurrence. The second objective was to assess [67Ga]Ga-THP-PSMA for molecular radiotherapy. Extremely high molar activity was achieved: 326 MBq/nmol (22% chelator occupancy). Despite this, the activity delivered to GCP(II)/PSMA expressing cells was low (max 0.1 Bq/cell) and the tracer showed rapid efflux. These findings were confirmed with in vivo studies showing poor retention of [67Ga]Ga-THP-PSMA in GCP(II)/PSMA-expressing prostate cancer tumours. These results suggest that the affinity and retention, but not the molar activity, limit the use of [67Ga]Ga-THP-PSMA for molecular radiotherapy. The third objective was to determine whether replacing the urea with a thiourea in the GCP(II)/PSMA targeting motif resulted in higher affinity. This was studied using the inhibitors Glu-C(O)-Glu and Glu-C(S)-Glu, the syntheses of which are described. The in vitro inhibition assays showed that the affinity was made much weaker by the presence of the thiourea (135 μM compared to 1.34 μM) and therefore this is not an effective strategy for improving affinity. Overall the THP-PSMA bioconjugate shows excellent radiolabelling properties, with both gallium-68 and gallium-67. [68Ga]Ga-THP-PSMA is a good PET imaging agent for prostate cancer however, improved affinity for GCP(II)/PSMA and retention of the tracer may potentially enhance the utility of [67Ga]Ga-THP-PSMA for molecular radiotherapy.
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Salem, Ahmed. "Validating non-invasive therapeutic lung cancer biomarkers." Thesis, University of Manchester, 2018. https://www.research.manchester.ac.uk/portal/en/theses/validating-noninvasive-therapeutic-lung-cancer-biomarkers(edeb97f1-b1d4-43a3-bafb-8c7e1fa9d8c7).html.
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Lung cancer is the leading cause of cancer death and a priority research area. There is an unmet need to develop biomarkers to enable patient selection and stratification in future lung cancer trials. This thesis aimed to validate non-invasive therapeutic lung cancer biomarkers. The investigated biomarkers were derived from imaging techniques used in routine healthcare (computed tomography and [18F]fludeoxyglucose (FDG) positron emission tomography (PET)) and research-domain imaging methods of hypoxia (multi-parametric magnetic resonance imaging (MRI) and [18F]fluoroazomycin arabinoside (FAZA) PET) and proliferation ([18F]fluorothymidine (FLT) PET), along with circulating biomarkers. These biomarkers were derived from one randomized controlled trial and 3 prospective pilot studies. I report for the first time the outcome of early limited stage (LS)- small cell lung cancer (SCLC), staged using the tumour, node and metastasis (TNM) staging system, within a randomized controlled trial. Early (TNM stage I-II) LS-SCLC patients achieve long-term survival with minimal acute side-effects following chemoradiotherapy and prophylactic cranial irradiation. This study guides patient management and benchmarks achievable outcomes in the era of modern radiotherapy. I report on the effects of different [18F]FAZA PET acquisition and analysis procedures on image parameters, comparing hypoxic volumes and fractions using fixed (>1.4, >1.2) and image-derived thresholds in non-small cell lung cancer (NSCLC) patients. I also investigate, for the first time, image repeatability and compare findings with a tissue-based hypoxia assessment in a patient subset, thus providing new [18F]FAZA PET validation data for the optimal application of this modality to derive potential hypoxia biomarkers. I present the world first oxygen-enhanced (OE) MRI clinical study to evaluate repeatability and show pharmacodynamic treatment effect, providing new technical and biological validation data for OE-MRI NSCLC hypoxia biomarkers. These results suggest that OE-MRI is feasible, well-tolerated, repeatable and has potential clinical utility as a biomarker in future NSCLC hypoxia-targeted therapy trials and radiotherapy dose painting studies. I present a pilot study that evaluated, to my knowledge, the largest blood biomarker panel in lung cancer patients. I show that baseline IL-1b and neutrophil count and early-treatment CYFRA 21-1 predict lung cancer radiotherapy response. CYFRA 21-1 and VCAM-1 correlated with [18F]FLT PET, highlighting for the first time a potential role of blood biomarkers as imaging surrogates. A trial proposal to investigate nimorazole (a hypoxic radiosensitizer) in TNM stage II-III NSCLC patients is presented. One of the trial aims is to validate (and ultimately qualify) [18F]FAZA PET, building on the thesis results. In summary, this thesis presents important new validation data for a range of therapeutic lung cancer biomarkers.
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Jerome, Hannah. "Outcomes of cancer bereavement therapeutic support groups." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1574714/.
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This thesis examines group interventions for bereavement. It is presented in three parts. Part I is a literature review of the effectiveness of group interventions for uncomplicated grief. Eleven studies met inclusion criteria. Overall, study quality was mixed. Ten of the 11 studies reported improvement in outcomes. Future research would benefit from greater homogeneity in theoretical approach and measurement and clearer intervention rationale. Part II presents a pre-post study of 27 participants who attended a six-session therapeutic cancer bereavement support group. A small waiting list group (N=11) was also used to estimate changes in outcomes over time with no intervention. At intervention completion, symptoms of grief intensity, PTSD, anxiety and depression were reduced and self-compassion was increased. At three-month follow-up, improvement in symptoms remained for grief, PTSD and depression. The waiting-list control group showed no change on any measures. The study provides preliminary evidence that a brief therapeutic group is an effective intervention for cancer bereavement. Part III is a reflection and critical appraisal on the experience of conducting the research described in Part II. It considers the strengths and limitations of conducting research in the voluntary sector and some measurement and ethical considerations of bereavement research. It concludes with reflections on researcher reflexivity and the emotional impact of conducting bereavement research.
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Elaskalani, Omar. "Platelet-cancer Crosstalk: Mechanisms and Therapeutic Implications." Thesis, Curtin University, 2019. http://hdl.handle.net/20.500.11937/77186.
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Platelets are small anucleate blood cells that are central to primary haemostasis. However, platelets are also implicated in cancer pathogenesis. This thesis showed that cancer cells promote thrombosis by activating platelets, and in turn, platelets provide cancer cells with growth factors to render cancer more aggressive and chemoresistant. The thesis demonstrated a therapeutic benefit of combined antiplatelet, ticagrelor, and chemo drugs, on cancer treatment.
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Funk, Marcia Sue Moffatt. "A survey of occupational therapy practitioners' interest in therapeutic horseback riding as a treatment modality." FIU Digital Commons, 1997. http://digitalcommons.fiu.edu/etd/3427.
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Three hundred and twenty four occupational therapy practitioners responded to a survey regarding their knowledge of, and interest in therapeutic horseback riding (THR). This survey addressed the research question "Why are there so few occupational therapy practitioners involved in therapeutic horseback riding?" The most frequent response cited by OT practitioners was a lack of horse knowledge followed closely by a lack of time. In addition, 181 schools offering occupational therapy programs responded to a survey which addressed the research question "Do American Occupational Therapy Association (AOTA) approved occupational therapy programs include therapeutic horseback riding as a treatment option in their curriculum?" The most frequent manner in which THR was included in a curriculum was through informal discussion or student presentation.
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Devlin, Kathleen Marie. "The effects of client and therapist variables on therapeutic modality selection: Family vs. individual therapy." Diss., The University of Arizona, 1993. http://hdl.handle.net/10150/186379.
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The study set out to examine the effect of therapist's orientation on his or her recommendations for individual or family based therapy. Other factors thought to influence the decision reached (i.e. experience, coursework, location of practice, perceived competency) were also explored. Seventy psychologists in the mental health field were presented with six clinical vignettes. The vignettes contained diagnoses or presenting problems that indicated either individual or family therapy, or contained insufficient information to clearly lead to a modality selection. It was found that the case vignette was the only significant variable affecting the modality or goals of the treatment recommendation. Biases in decision making among psychologists, based on orientation and areas of relative competence, were expected but not found. However, orientation did significantly affect the number of sessions recommended, with psychodynamic therapists recommending more therapy sessions than therapists from the other therapeutic orientations.
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Youniss, Fatma. "MULTI – MODALITY MOLECULAR IMAGING OF ADOPTIVE IMMUNE CELL THERAPY IN BREAST CANCER." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3323.
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Cancer treatment by adoptive immune cell therapy (AIT) is a form of immunotherapy that relies on the in vitro activation and/or expansion of immune cells. In this approach, immune cells, particularly CD8+ T lymphocytes, can potentially be harvested from a tumor-bearing patient, then activated and/or expanded in vitro in the presence of cytokines and other growth factors, and then transferred back into the same patient to induce tumor regression. AIT allows the in vitro generation and activation of T-lymphocytes away from the immunosuppressive tumor microenvironment, thereby providing optimum conditions for potent anti-tumor activity. The overall objective of this study is to: a) develop multi-modality (optical- and radionuclide-based) molecular imaging approaches to study the overall kinetics of labeled adoptively transferred T- lymphocytes in vivo, b) to non-invasively image and assess in-vivo, targeting and retention of adoptively transferred labeled T-lymphocytes at the tumor site. T-lymphocytes obtained from draining lymph nodes of 4T1 (murine breast cancer cell) sensitized BALB/C mice were activated in vitro with Bryostatin/ Ionomycin for 18 hours, and were grown in either Interleukin-2 (IL-2) or combination of Interleukin-7 and Interleukin-15 (IL-7/IL-15) for 13 days, (cells grown in IL-2 called IL2 cells, and cells grown in IL7/15 called IL7/15 cells). In order to validate the methodology and to offer future clinical translation, both direct and indirect cell labeling methods were expanded and employed. The first method was based on direct in vitro cell labeling by lipophilic near-infrared (NIR) fluorescent probe, 1,1- dioctadecyltetramethyl indotricarbocyanine iodide, (DiR), followed by intravenous (i.v.) injection into BALB/C mice for multi-spectral fluorescence imaging (MSFI). The second method was based on indirect labeling of T- lymphocytes through transduction of a reporter gene (cell cytoplasm labeling Herpes Simplex Virus type 1- thymidine kinase (HSV-1 tk). The product of this reporter gene is an enzyme (HSV-1TK) which phosphorylates a radio labeled substrate 2-fluoro-2-deoxy-1 β- D- arabinofuranosyl-5-iodouracil ([124I]-FIAU) for Positron Emission tomography (PET) imaging. ATP based cell viability assay, flow cytometry and interferon-γ (IFN-γ) ELISA were used to investigate if there are any changes in cell viability, proliferation and function respectively, before and after direct and indirect labeling. The results showed that cell viability, proliferation, and function of labeled 4T1 specific T-lymphocytes were not affected by labeling for direct labeling methods at DiR concentration of 320µg/ml. For the indirect labeling method, the viability and proliferation results showed that cell viability decreases as multiplicity of infectious (MOI) increases. In particular, at MOI of 10 almost all cells die 3 days post transduction. At MOI of 5, cells viability was ≤ 30% and at MOI of 2 was ≤ 60%. Cell viability was 80% at MOI of 1. The results of optical imaging were as follows: when the recipient mice with established 4T1 tumors were injected with DiR labeled 4T1 specific T-lymphocytes, the 4T1 specific T-lymphocytes (IL2 cells) infused into tumor-bearing mice showed high tumor retention, which peaked 3 or 6 days post infusion depending on the tumor size and persisted at the tumor site for 3 weeks. In contrast, IL7/15 cells showed lower signal at the tumor site and this peaked on day 8. On the other case when 4T1 tumor cells were implanted 1-week post-infusion of labeled T-lymphocytes. IL2 T-lymphocytes moved out of lymphoid compartments to the site of subsequent 4T1 inoculation within two hours and peaked on day 3 and the signal persisted for 2 more weeks. In contrast with infusion of IL7/15 cells, the signal was barely detected and did not show a similar trafficking pattern as with IL2 cells. The results of the indirect labeling method, PET reporter gene (PRG) system (HSV-1tk / [124I ] FIAU ) showed that both IL2 and IL7/15 cells were successfully transduced as verified ex vivo by real time PCR and western blot. T Cells transduction efficiency was assessed from cell uptake study in comparison to stable transduced Jurkat cells which have transduction efficiency of 100 %. Both IL2 and IL7/15 cells showed lower transduction efficiency (≤ 30%) compared to Jurkat cells. Consequently, PET imaging did not show a detectable signal of transduced T cells in vivo. Biodistribution study was carried out on day 3 post [124I]-FIAU injections. Results were consistent with the optical imaging results, except for IL7/15 cells. Transduced and untransduced IL2 and IL7/15 cells were labeled with DiR and injected ( i.v.) into Balb / C mice and then imaged by both imaging modalities (MSFI and PET) at the same time. MSFI images of transduced IL2 cell showed detectable signal starting from 2 hours, peaked at 72 hours and persisted up to 2 weeks, while IL7/15 cells were detectable at the tumor site starting at 24 hours, peaked at 72 hours and persisted up to 2 weeks. By the end of this study animals were dissected and tissue activities were counted using gamma counting and expressed as % Injected dose/gram of tissue (%ID/gm). Transduced IL2 and IL7/15 cells showed higher %ID/gm than other organs at lungs, liver, spleen, tumor, lymph nodes and bone/bone marrow. IL7/15 cells compared to IL2 cells showed higher %ID/gm at same organs. Neither IL2 nor IL7/15 untransduced DiR labeled cells showed any activity at tumor site, and their activities at other organs was very low compared to transduced cells. To investigate whether labeled T-lymphocytes will localize at tumor metastases or not, and to study the difference in their migration patterns to the tumor site versus tumor metastases, 4T1 tumor cells were successfully transduced with HSV-1tk as confirmed by RT-PCR , western blot and cell uptake study. Transduced 4T1 cells were implanted in the right flank or in the mammary fat pad of the mouse. Serial PET imaging was carried out in the third and fourth week post tumor implantation to know when the tumor will metastasizes. PET imaging showed only signal at the tumor site and no metastasis were detected.
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Khan, Tanweera S. "New Diagnostic and Therapeutic Approaches in Adrenocortical Cancer." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4243.
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Md, Tohid Siti Farah. "Synthesis of potential cancer therapeutic and diagnostic agents." Thesis, Cardiff University, 2011. http://orca.cf.ac.uk/54438/.
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The need to find novel anticancer agents with better potency, efficacy and safety are highly demanded. Therefore, the first part of the study was aimed to synthesise new compounds based on stilbenes, indole-based isoxazoles and tricyclic anilides as potential antitumour agents, which later will be evaluated for their anticancer properties. The syntheses of substituted stilbenes were achieved via catalyzed or uncatalyzed methods, yielding stilbene analogues in moderate to good yields. Preliminary antiproliferative studies on four cancer cell lines (prostate, non-small lung, colon and breast) demonstrated their antiproliferative potential in the micromolar range. Unfortunately, the stilbenes were unable to inhibit the Wnt-signaling pathway in colon cancer cells. Next, the synthesis of indole-based isoxazole analogues was achieved via two different methods affording the compounds in low to moderate yields. The compounds will later be tested for their anticancer properties. The synthesis of 3289-8625 (tricyclic anilides) analogues, compounds which showed potent inhibitory activites on the PDZ domain of Dishevelled (PDZ- Dvl) as an important component in the Wnt signaling pathway was also carried out. The synthesis was achieved via various methods which gave rise to the formation of two analogues, which showed better binding affinities towards the PDZ-Dvl compared to the parent compounds. Finally, the therapeutic potential of the stilbenes was expanded to the synthesis of stilbene-based analogues as novel positron emission tomography (PET) imaging probes especially for the detection of p-amyloid plaques in brain, which is a hallmark of Alzheimer's disease. The syntheses of stilbenes were sought using fluorine-19, using methods that can later be adapted for 18F-PET radiochemistry. The syntheses of stilbenes attached to 19F-linker were afforded in good yields. Stilbenes directly attached to potassium trifluoroborate were synthesised in moderate yield. Nevertheless, the attempt to synthesise stilbene derivatives attached to a potassium trifluoroborate linker using novel procedures failed.
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Chalfant, Cheryl Lynn. "Design guidelines for therapeutic gardens serving cancer patients." Virtual Press, 2002. http://liblink.bsu.edu/uhtbin/catkey/1231344.
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A growing body of research suggests that certain environmental conditions may positively contribute to the healing process. Consequently, the medical and design professions are now exploring how the medical environment - both indoors and out - can better support the health and well being of its patients and their caregivers. Landscape architects and environmental psychologists are contributing to the growing interest in healing environments by exploring the relationship between nature, therapeutic gardens, and patient healing.One result of this interest has been the formulation of design recommendations for therapeutic gardens serving specific populations such as those with Alzheimer's Disease, AIDS or psychiatric illnesses. However, little attention has been given to therapeutic gardens designed to meet the needs of cancer patients even though a number of such gardens already exist. The purpose of this project is to identify design guidelines for therapeutic gardens that support the health and well being of cancer patients and to use these guidelines to design a model garden.The research for this project focused on two areas. First, literature review and interviews with employees of Ball Memorial Hospital were used to establish a base knowledge of cancer, including the emotional, physical and psychological characteristics associated with it. Next, characteristics of healing environments for cancer patients were determined through literature review, review of case studies and interviews with Ball Memorial Hospital employees. Based upon this research, design guidelines were established for therapeutic gardens serving cancer patients and applied in a design for Ball Memorial Hospital's soon to be completed CancerCenter.Department of Landscape Architecture
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Chaneton, Barbara Julieta. "Targeting cancer cell metabolism as a therapeutic strategy." Thesis, University of Glasgow, 2014. http://theses.gla.ac.uk/5762/.
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In the past 15 years the field of cancer metabolism has burst providing vast quantities of information regarding the metabolic adaptations found in cancer cells and offering promising hints for the development of therapies that target metabolic features of cancer cells. By making use of the powerful combination of metabolomics and 13C-labelled metabolite tracing we have contributed to the field by identifying a mitochondrial enzymatic cascade crucial for oncogene-induced senescence (OIS), which is a tumour suppressive mechanism important in melanoma, linking in this way OIS to the regulation of metabolism. Furthermore, we have identified the dependency on glutamine metabolism as an important adaptation occurring concomitantly with the acquisition of resistance to vemurafenib (BRAF inhibitor) in melanoma, which opens the possibility to combine therapies targeting glutamine metabolism with BRAF inhibitors, in order to overcome or avoid the onset of resistance in melanoma. Using the same strategy we have discovered an important mechanism of interregulation between glycolysis and amino acid metabolism, identifying the glucose-derived amino acid serine as an activator of the main isoform of pyruvate kinase present in cancer cells, PKM2. In addition, we provide new insights into the mechanism of allosteric regulation of this complex protein and a better understanding of the way it regulates central carbon metabolism. In summary, our results open new possibilities for the development of cancer therapies that manipulate metabolic adaptations found in cancer cells in order to kill them specifically or halt their growth.
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Jiang, Shan. "Netrin-3, a novel therapeutic target in cancer." Thesis, Lyon, 2019. http://www.theses.fr/2019LYSE1344.
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Les protéines de la famille des nétrines ont principalement été caractérisées au cours du développement embryonnaire, comme des facteurs de guidage axonal. Néanmoins, ces protéines jouent aussi un rôle dans d’autres mécanismes, notamment certaines pathologies. La Nétrine-1 est ainsi une cible thérapeutique reconnue en cancérologie, puisque des molécules visant à bloquer son activité sont en cours de développement. Certains membres de cette famille restent néanmoins à caractériser. Nous avons pu mettre en évidence qu’une forte expression d’un de ces facteurs était corrélée avec un mauvais pronostique pour la survie des patients, dans deux pathologies cancéreuses. Nous avons émis l’hypothèse que ce facteur pouvait être une protéine de survie qui participe à l’agressivité des cellules cancéreusesThe proteins of the netrin family have been characterized mainly during embryonic development, as axonal guidance factors. However, these proteins also play a role in other mechanisms, including certain diseases. Netrin-1 is thus a recognized therapeutic target in oncology since molecules to block its activity are currently being developed. However, some members of this family have yet to be characterized. We were able to demonstrate that a strong expression of one of these factors was correlated with a poor prognosis for patient survival, in two cancer diseases. We hypothesized that this factor could be a survival protein that contributes to the aggressiveness of cancer cells
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Sherret, John, and Joshua Coleman. "Small Cell Medullary Thyroid Cancer: A Therapeutic Dilemma." Digital Commons @ East Tennessee State University, 2020. https://dc.etsu.edu/asrf/2020/presentations/57.
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Small cell variant of medullary thyroid carcinoma is an extremely rare histologic entity with a paucity of data. As such, there is a lack of clinical experience regarding this disease. In this case, a 52-year-old patient with small cell variant medullary thyroid carcinoma was experiencing intractable nausea, vomiting, and diarrhea. The initial workup was extensive yet unrevealing. He was refractory to all treatments. On further laboratory analysis, the calcitonin was substantially high and the thyroid stimulating hormone level was mildly elevated. This case is presented to highlight a possible treatment for this rare cancer through thyroxine suppression therapy. This case is presented due to the lack of literature available on small cell medullary thyroid carcinoma and also to discuss a possible direct relationship between thyroid stimulating hormone and calcitonin levels in this disease population.
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Forsberg, Ole. "Generation of Therapeutic T Cells for Prostate Cancer." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-100506.
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Lee, Kristy. "Targeting Copper: A Therapeutic Strategy In Lymphoma." Diss., The University of Arizona, 2013. http://hdl.handle.net/10150/294030.
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Non-Hodgkin lymphomas often arise at sites of chronic inflammation, exposing them to oxidative stress, or increased levels of reactive oxygen species (ROS). Increases in ROS are associated with tumor initiation, promotion and progression. Chronic exposure to ROS may promote the transformation of lymphocytes to lymphoma. Anti-apoptotic proteins such as Bcl-2 are commonly overexpressed in lymphoid malignancies. The protective function of Bcl-2 is partially dependent on its ability to regulate the redox environment. Adaptation to oxidative stress via the upregulation of anti-oxidant defense enzymes or upregulation of anti-apoptotic proteins appear to, in part, confer resistance to chemotherapeutics through their ability to regulate the redox environment. This suggests that using an agent to disrupt redox homeostasis has potential as a therapeutic strategy to circumvent these resistance mechanisms. The following studies examine the use of the copper chelator drug, ATN-224, to modulate the redox environment and circumvent the upregulation of anti-oxidant defense enzymes and anti-apoptotic proteins. These studies demonstrate that ATN-224 inhibits the primary anti-oxidant defense enzyme SOD1 and the redox-driven proton pump CcOX (complex IV in the electron transport chain). This inhibits the ability of SOD1 and CcOX to regulate the cellular and/or mitochondrial redox environment, respectively. ATN-224 treatment increases oxidative stress and induces peroxynitrite-dependent cell death. Furthermore, ATN-224 induces the release of AIF from the mitochondria, resulting in caspase-independent cell death. Collectively, these findings suggest that modulating the redox environment with ATN-224 has therapeutic potential in the treatment of non-Hodgkin lymphoma.
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Lee, W. M. Anne, and 李詠梅. "Therapeutic benefits of concurrent chemoradiotherapy for advanced nasopharyngeal carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B41290677.
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Tate, Tyler, and Tyler Tate. "Dual Modality Optical Coherence Tomography and Multispectral Fluorescence Imaging for Ovarian Cancer Detection." Diss., The University of Arizona, 2017. http://hdl.handle.net/10150/623156.
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Ovarian cancer is the deadliest gynecologic cancer for women. Diagnosis at the local stage leads to 91% 5-year survival rates, but only 15% of cases are detected early. Existing screening methods have proven ineffective in large clinical trials. Screening is complicated by the heterogeneity of the disease with multiple types of ovarian cancer originating both on the ovary and in the fallopian tube. Early stage cancer is too subtle for non-invasive imaging techniques such as ultrasound or magnetic resonance imaging. This study evaluates the feasibility and design of dual modality, multispectral fluorescence imaging (MFI) and optical coherence tomography (OCT) endoscopes for improved ovarian cancer screening. The study is broken up into three sections. In the first study MFI is validated in an ex vivo imaging study of human ovarian and fallopian tube tissue samples. Tissue autofluorescence excited by ultraviolet and blue wavelengths is shown to be a promising discriminator between normal and cancerous tissue. The second study combines OCT and MFI into a sub millimeter diameter endoscope designed to screen for ovarian cancer by screening inside the fallopian tube and at the ovary. The small size is required for screening the full length of the fallopian tube. MFI is implemented as a wide-field navigational imaging technique with high sensitivity complemented by high resolution structural depth imaging of OCT over a limited field of view. The final study presents a novel lens design for a scanning fiber endoscope with forward-viewing navigation and side-viewing OCT. A piezo tube is used to scan an optical fiber providing both the navigation channel’s illumination and OCT imaging. The design spatially separates the forward-viewing illumination from the OCT. As the piezo fiber circularly scans at its maximum deviation the OCT beam focus is rotationally scanned out the side of the endoscope tip by a rotationally symmetric double reflection in the cover plate.
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Bosco, Emily E. "RB suppressor modifies the therapeutic response of breast cancer." Cincinnati, Ohio : University of Cincinnati, 2006. http://www.ohiolink.edu/etd/view.cgi?acc%5Fnum=ucin1147202417.
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Thesis (Ph. D.)--University of Cincinnati, 2006.Title from electronic thesis title page (viewed . May 17, 2006). Includes abstract. Keywords: Retinoblastoma Tumor Suppressor; Breast Cancer; E2F; Tamoxifen; anti-estrogen resistance; DNA damage; cell cycle checkpoint. Includes bibliographical references.
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Schwartz, Timothy R. "Therapeutic single-stranded oligonucleotides in gene repair and cancer." Access to citation, abstract and download form provided by ProQuest Information and Learning Company; downloadable PDF file, 172 p, 2008. http://proquest.umi.com/pqdweb?did=1459919021&sid=13&Fmt=2&clientId=8331&RQT=309&VName=PQD.
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Maddocks, Matthew. "Therapeutic exercise in cancer cachexia : exploring approaches and outcomes." Thesis, University of Nottingham, 2010. http://eprints.nottingham.ac.uk/11112/.
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Cachexia is common in patients with incurable cancer, particularly of the lung and upper-gastrointestinal tract, and impacts adversely on treatment options, morbidity, quality of life and survival. Current management of cancer cachexia is inadequate and progress is required. This thesis explores the use of exercise as a proactive supportive therapy with a focus on maintaining physical function. The first piece of work was a systematic review of the use of therapeutic exercise in patients with or cured of cancer. Across 65 exercise studies, the median [IQR] rates of uptake, adherence and completion were 63 [33–80]%, 84 [72–93]% and 87 [80–96]% respectively, with no characteristic influencing the proportion of patients taking up or completing a programme. The main reasons reported for refusal were lack of interest or the impracticality of the programme and for withdrawal were medical complication or deterioration. Overall, only about half of patients offered an exercise programme completed one. This review highlighted a need to modify existing programmes or explore novel alternatives if exercise is to be acceptable to the majority of patients. The second study explored exercise preferences in patients with incurable cancer. A questionnaire was used to determine patients’ perceived capability and preparedness to undertake six different exercise programmes, each illustrated by video clips and accompanying text, and preferences for the delivery of the most preferred programme. All 200 patients considered themselves physically capable of undertaking an exercise programme and two-thirds were prepared to undertake one at that moment in time. The most preferred type of exercise was neuromuscular electrical stimulation (NMES) 36 [35−44]%, followed by walking 22 [16−30]% and resistance training 19 [13−26]% and the majority preferred to undertake exercise at home, alone and unsupervised. This survey suggested that it is realistic to offer therapeutic exercise programmes to patients with incurable cancer and provided rationale to explore NMES in this group. The third study was a randomised controlled pilot study of NMES in patients with non-small cell lung cancer. Sixteen patients were randomised to a control group, which received usual care, or NMES group, which received daily stimulation to the quadriceps for up to 30min (frequency 50Hz, on phase 11−25%) for four weeks. All patients found the NMES device acceptable and median (range) adherence to the recommended programme was 80% (69-100). In the NMES group, quadriceps muscle strength and free-living physical activity improved by a mean of 7.4 Newton metres (22%) and 136 steps (11%) respectively, whilst exercise endurance deteriorated by a mean of 20 metres (4%). This compared favourably with the control group however none of the differences were statistically significant. These findings suggested NMES was an acceptable type of exercise and that further study is warranted in patients with lung cancer. The final piece of work was a feasibility study into the use of a lightweight ActivPAL™ monitor to measure physical activity level. The aims were to determine if this form of assessment is acceptable to patients, the optimal period of monitoring and to explore the added value of the monitor's energy expenditure (EE) estimate over a simple step count. Sixty patients with lung or upper-gastrointestinal cancer wore a monitor for one week. All but one found the monitor acceptable and mean [95% CI] adherence was 98 [94−100] %. Mean daily step count and EE values measured over 2 and 4 days were significantly higher than those from 6 days (p<0.01). Step count was strongly related to stepping EE and non-stepping EE. The ActivPAL™ monitor was shown to be an acceptable method of assessing physical activity level. A mean daily step count obtained over 6 days was recommended for use in future cachexia studies. Collectively, this work supports the use of therapeutic exercise and highlights a particular role for novel approaches, e.g. NMES, which may be more acceptable to patients. Findings can be used to guide future research which ultimately will determine if therapeutic exercise can help patients with cancer to maintain their level of physical activity and independence for as long as possible.
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Femel, Julia. "Therapeutic Cancer Vaccines Targeting Molecules Associated with Tumor Angiogenesis." Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-229572.
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Induction of an endogenous antibody response by therapeutic vaccination could provide an alternative to cost-intensive monoclonal antibody-based treatments for cancer. Since the target of a cancer vaccine will most likely be a self-antigen, self-tolerance of the immune system must be circumvented. Using fusion proteins consisting of the self-antigen to be targeted and a part derived from a foreign antigen, it is possible to break tolerance against the self-antigen. Furthermore, a potent adjuvant is required to support an immune response against a self-molecule. Currently no adjuvant suitable for this purpose is approved for use in humans. This thesis describes the development of a therapeutic vaccine targeting the vasculature of tumors. As tumor cells have developed strategies to escape immune surveillance, targeting of molecules associated with the tumor stroma is an interesting alternative. The alternatively spliced extra domain-A and B (ED-A and ED-B) of fibronectin and the glycan-binding protein galectin-1 are selectively expressed during events of tumor angiogenesis. We have designed recombinant proteins to target ED-B, ED-A and galectin-1, containing bacterial thioredoxin (TRX) as a non-self part, resulting in TRX-EDB, TRX-EDA and TRX-Gal-1. Vaccination against ED-B induced anti-ED-B antibodies and inhibited growth of subcutaneous fibrosarcoma. Immunization against ED-A decreased tumor burden and reduced the number of lung metastases in the MMTV-PyMT model for metastatic mammary carcinoma in a therapeutic setting. Analysis of the tumor tissue from ED-B and ED-A-immunized mice indicated an attack of the tumor vasculature by the immune system. Finally, we show that galectin-1 immunization reduced tumor burden and increased leukocyte numbers in the tumor tissue. Galectin-1 is pro-angiogenic and immunosuppressive, and therefore allows simultaneous targeting of fundamental characteristics of tumorigenesis. We furthermore show that the biodegradable squalene-based Montanide ISA 720 combined with CpG oligo 1826 (M720/CpG) is at least as potent as Freund’s adjuvant with respect to breaking self-tolerance, when comparing several immunological parameters. Freund’s is a potent but toxic adjuvant used in the majority of preclinical studies. The work presented in this thesis shows that therapeutic cancer vaccines targeting the tumor vasculature are a feasible and promising approach for cancer therapy.
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Agrawal, Vibhuti. "Dissecting the molecular mechanisms of therapeutic resistance in cancer." Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/112493.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2017.Cataloged from PDF version of thesis.
Includes bibliographical references.
Therapeutic resistance continues to be a persistent challenge in medical oncology. In clinical settings, resistance can occur at the beginning of treatment, or may be acquired after an initial clinical response to the therapy. Several mechanisms of drug resistance have been described in cancer, including alterations in the drug transport and metabolism process, mutations in drug-target, activation of bypass signaling pathways, inhibition of cell-death pathways, and induction of an epithelial to mesenchymal transition (EMT) in response to cytotoxic or targeted therapies. In this study, I have investigated the molecular mechanisms underlying ZEB 1-induced EMT and established a new computational framework that uses inter-animal heterogeneity to identify drivers responsible for variable phenotypic responses across different animals. EMT describes a cell-state switching process wherein epithelial cells lose their tight cell-cell junction contacts, and acquire the ability to migrate and invade the surrounding stroma to enter into blood circulation. Given the widespread role of EMT in drug resistance, it is imperative to identify therapeutic strategies to inhibit this transition. To identify druggable targets to block EMT progression, and therefore overcome EMT-mediated therapeutic resistance, I studied the effects of ZEB 1 expression on cellular signaling networks. By quantifying changes in tyrosine phosphorylation at different time points during ZEB 1-induced EMT, I found that Src family kinases (SFKs) were activated within 24 hours of ZEB 1 expression. Inhibition of SFKs blocked not only ZEB 1-induced EMT, but also EMT initiated by TGFp- and EGF signaling pathways in both breast and NSCLC cell-lines. SFK inhibition also prevented EGFR inhibitor-induced EMT and drug resistance in NSCLC cells both in vitro and in vivo. Mechanistically, SFK activation stabilized ZEBI by promoting ERK1/2-mediated phosphorylation on three serine residues, S583, S646, and S679. Consequently, MEK inhibition phenocopied the effects of blocking SFK activity with regards to decreasing stability of ZEB 1 and inhibiting ZEB 1-induced EMT. These results provide a new therapeutic application of SFK inhibitors as a potential anti-EMT therapy, to enhance the susceptibility of cancer cells to chemo- or targeted therapies. In the second part of this thesis, I have described a computational framework that leverages inter-animal heterogeneity to identify molecular mechanisms underlying variable phenotypic responses across different animals. Substantial inter-animal variability in phenotypes within the same treatment group, limits our ability to draw conclusions or gain meaningful insights about a biological process by simply averaging the data. To identify molecular drivers for heterogeneous phenotypic responses, I have established a method where each animal is considered as an individual entity whose phenotypic response is dependent on the state of its underlying signaling networks. As a proof of concept, I have used this method to successfully predict the resistance mechanisms of CDK4/6 inhibitor, palbocilib in two GBM PDX and one MPNST PDX models. The GBM6 model activated EGFR signaling upon treatment with palbociclib whereas the GBM22 and MPNST3 models activated SFKs and PDGFRa signaling in resistant tumors. Across all three PDX tumor models, treatment with combination therapies, consisting of palbociclib and an inhibitor targeting the activated bypass signaling pathway, substantially prolonged survival of mice. Thus, these results suggest that inter-animal variability can be used as a tool to predict drivers for a specific phenotypic response across different treatment conditions.
by Vibhuti Agrawal.
Ph. D.
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Larkin, James Michael George. "Modelling hyperacute rejection as a therapeutic approach to cancer." Thesis, Institute of Cancer Research (University Of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.415089.
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Hicks, Mellissa. "Signaling Networks as Possible Therapeutic Implications in Breast Cancer." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1405945861.
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Yassen, Mohammed Omar Abdelaziz [Verfasser]. "Human Cytomegalovirus (HCMV)-based Therapeutic Cancer Vaccines / Mohammed Yassen." Berlin : Freie Universität Berlin, 2020. http://d-nb.info/1218077360/34.
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Hamed, Hossein. "MDA-7/IL-24; A PROMISING CANCER THERAPEUTIC AGENT." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/2847.
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Glioblastoma multiforme (GBM) is an aggressive cancer that affects millions of patients per year. Conventional therapies combining chemotherapeutic agents with radiation can only extend survival by a few months; therefore, there is a dire need for an effective means of treating this deadly disease. Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24), currently in the early stages of FDA pre-IND drug trials, has proven to be an effective cancer specific cytokine, able to trigger the onset of mitochondrial dysfunction and/or autophagy. GBM’s have mutations that often result in the activation of cytoprotective cell signaling pathways, preventing cancer therapeutics and even MDA-7/IL-24 treatments from being effective. Since the discovery of MDA-7/IL-24 a number of groups have shown toxic effects in a variety of tumor cells. However, the lethality of MDA-7/IL-24 is not enough to eradicate the tumor. We hypothesized two xxiii rationales for this minimalistic effect. First, the MDA-7/IL-24 gene delivery mechanisms are not efficient or second, active pro-survival pathways are playing a role in protection. Here we have shown that the inhibition of cytoprotective cell-signaling pathways using small molecule inhibitors of mitogen-activated extracellular regulated kinase (MEK)1/2 and phosphatidyl inositol 3-kinase (PI3K) or AKT; mammalian target of rapamycin (mTOR) and MEK1/2; HSP90 inhibitor 17AAG; and the autophagy-inducing drug OSU-03012 (AR-12), enhances the toxicity of MDA-7/IL-24. In addition, the use of a modified recombinant adenovirus comprised of the tail and shaft domains of a serotype 5 virus and the knob domain of a serotype 3 virus expressing MDA-7/IL-24, Ad.5/3-mda-7, proved to be a more effective, CAR-independent means of infecting and killing GBM cells in vitro and in vivo when compared to Ad.5-mda-7. Collectively, our data demonstrate that the induction of autophagy and mitochondrial dysfunction by a combinatorial treatment approach represents a potentially viable strategy to kill primary human GBM cells.
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Ward, Nathan Patrick. "Therapeutic Modulation of Cancer Metabolism with Dichloroacetate and Metformin." Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/6778.
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The robust glycolytic metabolism of glioblastoma multiforme (GBM) has proven them susceptible to increases in oxidative metabolism induced by the pyruvate mimetic dichloroacetate (DCA). Recent reports demonstrate that the anti-diabetic drug metformin enhances the damaging oxidative stress associated with DCA treatment in cancer cells. We sought to elucidate the role of metformin’s reported activity as a mitochondrial complex I inhibitor in the enhancement of DCA cytotoxicity in the VM-M3 model of GBM. We demonstrated that metformin potentiated DCA-induced superoxide production and that this was required for enhanced cytotoxicity towards VM-M3 cells with the combination. Similarly, rotenone enhanced oxidative stress resultant from DCA treatment and this too was required for the noted augmentation of cytotoxicity. Adenosine monophosphate kinase (AMPK) activation was not observed with the concentration of metformin required to enhance DCA activity. Moreover, addition of an activator of AMPK did not enhance DCA cytotoxicity, whereas an inhibitor of AMPK heightened the cytotoxicity of the combination. We also show that DCA and metformin reduce tumor burden and prolong survival in VM-M3 tumor-burdened mice as individual therapies. In contrast to our in vitro work, we did not observe synergy between DCA and metformin in vivo. Our data indicate that metformin enhancement of DCA cytotoxicity is dependent on complex I inhibition. Particularly, that complex I inhibition cooperates with DCA-induction of glucose oxidation to enhance cytotoxic oxidative stress in VM-M3 GBM cells. This work supports further investigation and optimization of a DCA/metformin combination as a potential pro-oxidant combinatorial therapy for GBM.
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Filipovic, Aleksandra. "Nicastrin as a novel therapeutic target in breast cancer." Thesis, Imperial College London, 2011. http://hdl.handle.net/10044/1/14694.
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Nicastrin is an essential component of the gamma-secretase (GS) enzyme complex, required for its synthesis and recognition of substrates for proteolytic cleavage. The purpose of this study was to investigate whether nicastrin has a prognostic value or the potential as a therapeutic target in breast cancer. Tissue microarrays (TMAs) (n = 1050), and breast cancer cell line analyses confirmed that nicastrin expression was upregulated in breast cancer compared to normal breast cells. In TMA patient samples, high nicastrin expression was observed in 47.5% of cases and correlated with worse breast cancer specific survival in the ERα negative cohort. Transient and stable gene silencing of nicastrin in vitro, resulted in the disruption of the GS complex activity and a decrease in Notch1 cleavage. Nicastrin silencing in invasive MDA-MB-231 and HCC1806 cells resulted in the loss of vimentin expression and a reduction in cell invasion, which was concomitant with the formation of cell-cell junctions, as well as cellular repolarisation. In a population of breast cancer cells harbouring the cancer stem cell phenotype (CD44+/CD24-), nicastrin depletion abrogated expression of the epithelial to mesenchymal (EMT) markers, vimentin, SIP1 and Snail. Furthermore, nicastrin overexpression in the non-malignant MCF10A breast cells increased expression of other GS components, Notch activation, vimentin expression and invasive capacity. These data indicate that nicastrin can function to maintain the EMT transition during breast cancer progression. We have developed anti-nicastrin polyclonal and monoclonal antibodies and have shown that they are able to decrease the invasive and proliferative capacity of MDA-MB-231 breast cancer cells in vitro. In order to dissect the role of nicastrin within the GS complex from its presumed GS-independent signaling role in breast cancer cells, we have performed gene array analyses and identified a subset of genes that are nicastrin-dependent and are not affected by silencing of the Notch receptors. The data presented in this thesis therefore support our hypothesis that an antagonising monoclonal antibody could be suitable to inhibit nicastrin as a potential therapeutic target in invasive breast cancer.
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Yassen, Mohammed [Verfasser]. "Human Cytomegalovirus (HCMV)-based Therapeutic Cancer Vaccines / Mohammed Yassen." Berlin : Freie Universität Berlin, 2020. http://d-nb.info/1218077360/34.
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Su, Hsin-Yuan. "Therapeutic Potential of EGFR Derived Peptides in Breast Cancer." Diss., The University of Arizona, 2013. http://hdl.handle.net/10150/293486.
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The epidermal growth factor receptor (EGFR) belongs to the erbB family of receptor tyrosine kinases which consists of four members (EGFR, ErbB2, ErbB3 and ErbB4). Upon ligand binding, the EGFR is capable of dimerization with other erbB receptors and propagates signals regulating a diverse array of cellular physiologies, including cell growth, migration and survival. Dysregulation of the EGFR is important for development and progression of different types of cancers, including breast cancer. Breast cancer is the second leading cause of cancer death in women. EGFR overexpression has been observed in about 15% of all breast cancers. Moreover, in triple negative breast cancer (TNBC), which is a more aggressive type of breast cancer and lacks effective therapies, up to 50% of tumors are found to overexpress EGFR. Targeted therapy against EGFR has been used in TNBC. However, limited efficacy has been observed in TNBC due to intrinsic and acquired resistant mechanisms. In order to overcome this issue, we have developed two novel therapeutic peptides derived from the nuclear localization signal (NLS) sequence and juxtamembrane domain of EGFR and investigated their efficacy in regard to inhibiting EGFR translocation and activation in TNBC. EGFR has been found to translocate into the nucleus and nuclear EGFR can affect gene transcription, cell proliferation, stress response and DNA repair through interacting with different components in the nucleus. Importantly, these functions of nuclear EGFR correlate with cancer prognosis and therapeutic resistance. We found that an EGFR NLS-derived peptide (ENLS peptide) could inhibit activated EGFR (pY845) undergoing nuclear translocation. We also showed that this ENLS peptide sensitized breast cancer cells to AG1478 (EGFR tyrosine kinase inhibitor) treatment. The juxtamembrane domain of EGFR regulates its trafficking to the nucleus and mitochondria, interaction with calmodulin and calcium signaling, and participates in dimerization and activation of EGFR. These non-traditional kinase related functions of EGFR represent a novel target for EGFR therapy. We found that a mimetic peptide of the juxtamembrane domain of EGFR (EJ1 peptide) could effectively inhibit EGFR activation through promoting inactive dimer formation. It could also effectively kill cancer cells through processes of apoptosis and necrosis. Mechanistically, this EJ1 peptide affects membrane integrity thereby leading to calcium influx, disruption of mitochondrial membrane potential and reactive oxygen species (ROS) accumulation. Importantly, EJ1 peptide appeared to be effective in inhibition of tumor growth and metastasis in a transgenic mouse model of breast cancer and showed no observable toxicity. ErbB3, another member of the erbB family, represents an important driver of the parallel signaling pathway to EGFR as well as a key regulator of PI3K/AKT activity which is important for therapeutic resistance. ErbB3 has been shown to interact with MUC1. The interaction between MUC1 and EGFR promotes EGFR stability through recycling of receptors. We found that MUC1 expression also affected ErbB3 activity and stability through ErbB3/EGFR/MUC1 complex formation. In conclusion, we demonstrated that two EGFR-derived peptides, working through novel strategies, represent a new foundation of effective therapeutic agents to breast cancer. ErbB3/EGFR/MUC1 complex formation under MUC1 expression also represents a druggable target for ErbB3 activity and stability.
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Abel, Mark Joshua. "Novel therapeutic and diagnostic ultrasound techniques in cancer management." Thesis, Imperial College London, 2016. http://hdl.handle.net/10044/1/47909.
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Introduction: The aim of this thesis is to assess novel therapeutic and diagnostic ultrasound techniques in cancer management. A drive to improve prognosis in cancer patients has resulted in a vast array of recent medical advances and new approaches using ultrasound technology may enhance outcome in patients with a diagnosis of malignancy. Methods: A new 256 element random phased-array high intensity focused ultrasound (HIFU) device was designed, developed and tested for use in treating hepatic tumours. An existing intra-cavitary HIFU transducer (Sonablate 500®) currently under investigation for use in prostate cancer was adapted to determine safety and efficacy in the treatment of other pelvic malignancies. Doppler, dynamic contrast-enhanced ultrasound (DCE-US) and shearwave elastography (SWE) were used to assess changes in perfusion and elasticity respectively of hepatic tumours and liver parenchyma in patients undergoing therapy for primary or secondary liver malignancy with cytotoxic chemotherapy, selective internal radiation therapy and biological agents. Measurements were correlated with serum tumour and inflammatory markers and hepatic cancer volume. Results: The new HIFU device was able to cause rapid and directed large volume tissue ablations deep to a simulated rib cage in an ex vivo setting. The Sonoblate® device was safely used for symptomatic relief in a patient with cervical cancer, although device design limitations prevented successful implementation in rectal carcinoma. In multiple circumstances, Doppler, DCE-US and SWE were able to prognosticate outcomes to cancer therapy at pre-treatment and 2-week time points and showed a level of correlation with serum markers and tumour volume. Conclusion: Novel ultrasound techniques, including HIFU, Doppler ultrasound, DCE-US and SWE show promise in both the treatment and response monitoring of patients diagnosed with malignancy.
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Dudakovic, Amel. "Geranylgeranyl diphosphate synthase as a novel cancer therapeutic target." Diss., University of Iowa, 2010. https://ir.uiowa.edu/etd/795.
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The isoprenoid biosynthetic pathway is targeted in the treatment of several diseases, including hypercholesteremia and bone related disorders. Farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP) are isoprenoid biosynthetic pathway intermediates that are utilized during post-translational modification of proteins termed farnesylation and geranylgeranylation, respectively, together known as prenylation. The Ras and Rho GTPase family members are examples of proteins that are prenylated. Prenylation is essential for proper membrane localization and function of these small GTPases. Activating mutations or over-expression of these proteins promote oncogenic events, such as increased proliferation and migration.
Studies have demonstrated that farnesyl transferase inhibitors and geranylgeranyl transferase inhibitors possess anti-cancer effects in humans and animal models of cancer, respectively. An alternative way to impair protein prenylation is through the depletion of FPP and GGPP. Statins and nitrogenous bisphosphonates (NBPs) deplete FPP and GGPP leading to impaired protein prenylation by inhibiting HMG-CoA Reductase (HMGCR) and FPP synthase (FDPS), respectively. These drugs have been shown to induce apoptosis, inhibit cancer cell migration, and induce cell cycle arrest. The anti-cancer effects of statins and NBPs can be prevented by GGPP addition, suggesting that GGPP depletion may be the mechanism by which these agents interfere with cancer cell survival.
We and our collaborators have developed bisphosphonate inhibitors of GGPP synthase (GGDPS), an enzyme that produces GGPP from the substrates FPP and isopentenyl pyrophosphate.
The goal of this research was to identify novel GGDPS inhibitors and to assess the effects of specific inhibition of GGDPS on cancer cell survival and function. Two aromatic bisphosphonates were identified as potent inhibitors of GGDPS in enzyme and cellular assays. Apoptosis hallmarks such as PARP cleavage and DNA fragmentation demonstrated that GGDPS inhibition induces apoptosis in K562 chronic myeloid leukemia cells through GGPP depletion and FPP accumulation. Isobologram analysis and enhanced impairment of protein geranylgeranylation showed that GGDPS inhibition is synergistic with the inhibition of HMGCR. Migration assays, transwell assay and large scale digital cell analysis system microscopy, demonstrated that GGDPS inhibition interferes with MDA-MB-231 breast cancer cell migration. Increased LC3-II expression showed that FDPS and GGDPS inhibition induces autophagy in PC3 prostate and MDA-MB-231 breast cancer cells. Inhibition of autophagy enhances the toxic effects of GGDPS inhibition as measured by MTT assay. Propidium iodine staining of DNA and immunostaining of cell cycle proteins such as p27 did not show significant effects of GGDPS inhibition on cell cycle progression. Importantly, exogenous addition of GGPP prevented most of the effects observed with GGDPS inhibition, suggesting specific inhibition of GGDPS by our bisphosphonate inhibitors. The data obtained herein suggest that GGDPS can be targeted to interfere with the progression of cancer cells.
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Gross, Brett Patrick. "Therapeutic vaccination for the treatment of metastatic breast cancer." Diss., University of Iowa, 2018. https://ir.uiowa.edu/etd/6119.
Full textAbstract:
Metastatic breast cancer is a leading cause of cancer-related mortality worldwide. While existing interventions are effective at treating localized tumors, disseminated malignancies remain incurable. Vaccine-induced anti-tumor immunity is a promising approach for treating disseminated tumors, as immune responses are systemic, have antigen-restricted cytotoxicity, and generate protective immune “memory” populations.
Our group has developed a novel heterologous prime/boost vaccine protocol that treats established 4T1 murine mammary tumors. Briefly, this approach entails a vaccine prime consisting of tumor lysate antigens encapsulated within poly(lactic-co-glycolic) acid (PLGA) microparticles (MPs). The vaccine prime was followed by a vaccine boost consisting of tumor lysates plus adjuvants. Spontaneous 4T1 lung metastasis was evaluated at a pre-determined endpoint in vaccinated versus untreated mice. Vaccinated mice demonstrated significant, but incomplete, reductions in metastatic tumor burdens relative to untreated control mice.
Encouraged by these results, we evaluated additional vaccine variations with the goal of improving therapeutic responses. The addition of immunomodulatory chemotherapy or checkpoint blockade immunotherapy failed to significantly improve the initial vaccine’s efficacy. Conjugation of streptavidin/biotin complexes to the PLGA MP significantly improved vaccine efficacy, with vaccinated mice demonstrating 88% less metastatic tumor burdens than their untreated counterparts. These findings illustrate that vaccines based upon PLGA MP-mediated delivery of tumor lysates can form the basis of an effective treatment for metastatic breast cancer and suggest that similar approaches may be both efficacious and well-tolerated in the clinic.
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Thomas, Beverley Jayne. "Gene therapy of melanoma : therapeutic and pharmaceutical investigations." Thesis, University of Bath, 1997. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338377.
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Uitterhoeve, Apollonia Léonie Joséphine. "Radiotherapy and Cisplatin: outcome of combined modality treatment in non-small cell lung cancer." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2007. http://dare.uva.nl/document/47061.
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Lam, Chi-leung David, and 林志良. "Oncogenic mutations as biomarkers and therapeutic targets in lung cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/207610.
Full textAbstract:
Oncogenic mutations in lung cancer further our knowledge about cancer initiation and progression, and may guide personalized treatment. The fact that targeted therapy is most effective in subsets of patients with defined molecular targets indicates the need for classification of clinically-related molecular tumor phenotypes based on the presence of oncogenic mutations, including EGFR mutations and EML4-ALK rearrangements.
The identification of EGFR mutations, in up to half of lung adenocarcinomas in Asians, could predict clinical sensitivity to tyrosine kinase inhibitor (TKI). However, testing for mutations is not always possible due to tumor tissue availability. The therapeutic decision sometimes remains a clinical one especially for elderly lung cancer patients but no known mutation status. We studied the survival outcomes of targeted therapy versus conventional chemotherapy in elderly patients with lung cancer when we did not yet have routine EGFR mutation testing and demonstrated comparable survival outcomes in targeted therapy compared to chemotherapy, implying that survival with targeted therapy could be better if the treatment population could be selected with EGFR mutations.
Though testing for EGFR mutation in tumor biopsy have later become routine practice and remains the accepted reference for therapeutic decision, the detection of EGFR mutations in plasma DNA with high diagnostic performance will be useful adjunct for diagnostic and therapeutic monitoring. Among patients with EGFR mutations in tumor biopsy, the concurrent detection of EGFR mutation in plasma DNA was found to confer a less favorable prognosis in terms of overall survival than those patients with EGFR mutations in tumor biopsy but the corresponding mutation was not detected in plasma.
Other oncogenic mutations with therapeutic implications in lung tumors are yet to be fully explored, like ALK, KRAS, ROS1 or NTRK1 mutations. It is not exactly the tumor – but the mutations in the tumor that need to be explored with reference to clinical behavior. Even with EGFR mutation with well-established clinical implications, further exploration into its mechanistic functions will help in understanding of drug resistance. Lung cancer cell lines established from patients with known mutation profiles could be useful tools for studying the biology of known molecular targets as well as for therapeutic testing. Four new lung adenocarcinoma and one mesothelioma cell lines were established from patients with different clinical characteristics and oncogenic mutation profiles. These cell lines with defined mutation profiles will provide tools for exploration of lung cancer and mesothelioma biology with respect to molecular therapeutic targets.
The Large Tumor Suppressor 2 (LATS2) gene was a differentially expressed gene between EGFR mutant and wildtype lung adenocarcinomas. The differential LATS2 expression levels were predictive of survival in patients with resected lung AD and may modulate tumor growth via different signaling pathways in EGFR mutant and wild-type tumors.
The identification of oncogenic mutations has led to a new paradigm of targeted therapy in lung cancer. Further improvements in outcome of lung cancer management will stem from research into the biology of oncogenic mutations and their clinico-pathological correlations, which would fuel parallel development of clinically efficacious targeted therapies.published_or_final_version
Medicine
Master
Doctor of Medicine
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Matthewson, Kenneth. "Studies on therapeutic neodymium YAG laser endoscopy." Thesis, University of Newcastle Upon Tyne, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.241407.
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Carrington, Simon. "Polyamine conjugates with potential as therapeutic targets." Thesis, University of Bath, 1998. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268208.
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Karst, Alison Marie. "Novel therapeutic targeting of apoptosis and survival pathways in melanoma." Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/2473.
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Cutaneous malignant melanoma is an aggressive form of skin cancer, characterized by strong chemoresistance and poor patient prognosis. The molecular mechanisms underlying its resistance to chemotherapy remain unclear but are speculated to involve dysregulation of apoptosis and reinforcement of survival signaling. In this work, we show that aberrant expression of two key proteins, PUMA and p-Akt, is associated with melanoma tumor progression and poor patient survival. We report that PUMA expression is reduced in melanoma tumors compared to dysplastic nevi, while p-Akt expression is elevated in melanoma tissue compared to dysplastic nevi. We propose a two-pronged therapeutic strategy of (1) boosting PUMA expression and (2) inhibiting Akt phosphorylation. We demonstrate that exogenous overexpression of PUMA, via adenoviral-mediated gene expression (ad-PUMA), forces melanoma cells to undergo rapid mitochondrial-mediated apoptosis in vitro. We also report that a small molecule Akt inhibitor, API-2, greatly inhibits melanoma cell growth in vitro. Using a SCID mouse melanoma xenograft model, we show that combination treatment of ad-PUMA and API-2 dramatically suppresses tumor growth in an additive manner, leading to over 80% growth inhibition compared to controls. We also investigate the role of NF-κB overexpression in melanoma. Our lab previously reported that expression of the p50 subunit of NF-κB, in particular, correlates with melanoma progression and poor patient survival. Here, we use cDNA microarray analysis to show that p50 overexpression upregulates IL-6 in melanoma cells. We further demonstrate that p50-mediated IL-6 expression stimulates the growth of endothelial cells in vitro and promotes angiogenesis in vivo. This work supports the hypothesis that melanoma cells exploit multiple mechanisms to sustain a survival advantage, including: 1) suppression of apoptosis (via PUMA down-regulation), 2) increased activation of survival pathways (via increased p-Akt), and 3) upregulation of pro-angiogenic factors (via p50-mediated IL-6 induction). This work suggests that the specific targeting of one or more key mediators of these processes may be an effective therapeutic strategy for treating malignant melanoma.
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Jarman, Paul J. "Mono and dinuclear ruthenium complexes as anti-cancer therapeutic leads." Thesis, University of Sheffield, 2015. http://etheses.whiterose.ac.uk/12213/.
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This thesis details chemistry and cell biology based interdisciplinary studies on a series of ruthenium based biomolecular probes that were synthesised and investigated for their anti-cancer properties. The previously reported mononuclear ruthenium-based [(phen)2Ru(tpphz)]2+ and three related new complexes were synthesised as a series to explore DNA binding. Binding to genomic DNA in vitro was confirmed for all complexes utilising their luminescence properties – specifically the DNA light switch effect via aqueous luminescence titrations. Cellular activity in the model of cisplatin sensitive/resistant A2780/A2780cis human ovarian carcinoma was then studied, with IC50 concentrations determined for each complex in each cell line and adequately repeated. This revealed a clear series of toxicities comparable to the level of cisplatin, furthermore a variety of positive and negative cross resistance profiles were observed. Time lapse microscopy data was then obtained for each complex and cell line permutation to visualize the mode of cell death, and a proteomic study was conducted with the aim of gathering more mechanistic detail behind the cell death pathway. After optimisation of a consistent workable protocol, photocytotoxicty was also investigated. Although this work was primarily with the ruthenium-rhenium and ruthenium-platinum binuclear complexes of the original series, further systems incorporating ruthenium-rhenium molecules were also investigated. Interestingly, these studies revealed contrasting phototoxic activity and a particularly impressive phototoxic index score for a Ru2Re2 macrocyclic cation.
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Makhani, Kiran, and Kiran Makhani. "Mechanism of Action of ERBB Decoy Cancer Therapeutic Peptide SAH5." Thesis, The University of Arizona, 2017. http://hdl.handle.net/10150/626139.
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Breast cancer is the most prevalent type of cancer and second leading cause of death in women. Among others, the triple negative breast cancer (TNBC) is the most invasive as it has the highest recurrence and death rates with no targeted therapeutic available thus far. Epidermal Growth Factor Receptor (EGFR) is one of the important targets as more than fifty percent of the TNBC overexpress it but all the therapies designed against it have failed to show significant results. The juxtamembrane domain of EGFR has been explored comparatively recently and has been used to design a decoy peptide with the anticipation to affect the EGFR downstream functions. Previous research has shown it to cause cell death in cancer cells. This study is aimed towards deciphering the mechanism of action of the stapled form of this decoy peptide-SAH5. It presents evidence that the peptide leads to an immediate intracellular calcium release from the Inositol 1,4,5 triphosphate on the endoplasmic reticulum, an inhibition of which can rescue SAH5 induced cell death. The study also demonstrate that the peptide is able to increase the production of Reactive Oxygen Species (ROS) in mitochondria, part of which is triggered by the peptide-induced calcium release.